Update on the Chemopreventive Effects of Ginger and its Phytochemicals

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Update on the Chemopreventive Effects of Ginger andits PhytochemicalsManjeshwar Shrinath Baliga a , Raghavendra Haniadka b , Manisha Maria Pereira c , JasonJerome D’Souza b , Princy Louis Pallaty d , Harshith P. Bhat e & Sandhya Popuri fa Research and Development, Father Muller Medical College, Father Muller Hospital Road,Kankanady, Mangalore, 575002, Karnataka, Indiab Father Muller Medical College, Father Muller Hospital Road, Kankanady, Mangalore,575002, Karnataka, Indiac Department of Pathology, Father Muller Medical College, Father Muller Hospital Road,Kankanady, Mangalore, 575002, Karnataka, Indiad Department of Pharmacology, Father Muller Medical College, Father Muller Hospital Road,Kankanady, Mangalore, 575002, Karnataka, Indiae Research Centre, Maharani Lakshmi Ammani Women's College, Malleswaram 18th Cross,Bangalore, 560012, Karnataka, Indiaf Sri Siddhartha Medical College, Tumkur, 572102, Karnataka, IndiaVersion of record first published: 15 Jun 2011.

To cite this article: Manjeshwar Shrinath Baliga , Raghavendra Haniadka , Manisha Maria Pereira , Jason Jerome D’Souza ,Princy Louis Pallaty , Harshith P. Bhat & Sandhya Popuri (2011): Update on the Chemopreventive Effects of Ginger and itsPhytochemicals, Critical Reviews in Food Science and Nutrition, 51:6, 499-523

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Critical Reviews in Food Science and Nutrition, 51:499–523 (2011)Copyright C©© Taylor and Francis Group, LLCISSN: 1040-8398 print / 1549-7852 onlineDOI: 10.1080/10408391003698669

Update on the ChemopreventiveEffects of Ginger and itsPhytochemicals

MANJESHWAR SHRINATH BALIGA,1 RAGHAVENDRA HANIADKA,2

MANISHA MARIA PEREIRA,3 JASON JEROME D’SOUZA2, PRINCY LOUISPALLATY,4 HARSHITH P. BHAT,5 and SANDHYA POPURI6

1Research and Development, Father Muller Medical College, Father Muller Hospital Road, Kankanady, Mangalore 575002,Karnataka, India2Father Muller Medical College, Father Muller Hospital Road, Kankanady, Mangalore 575002, Karnataka, India3Department of Pathology, Father Muller Medical College, Father Muller Hospital Road, Kankanady, Mangalore 575002,Karnataka, India4Department of Pharmacology, Father Muller Medical College, Father Muller Hospital Road, Kankanady, Mangalore 575002,Karnataka, India5Research Centre, Maharani Lakshmi Ammani Women’s College, Malleswaram 18th Cross, Bangalore 560012, Karnataka,India6Sri Siddhartha Medical College, Tumkur 572102, Karnataka, India

The rhizomes of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger, is one of the most widely usedspice and condiment. It is also an integral part of many traditional medicines and has been extensively used in Chinese,Ayurvedic, Tibb-Unani, Srilankan, Arabic, and African traditional medicines, since antiquity, for many unrelated humanailments including common colds, fever, sore throats, vomiting, motion sickness, gastrointestinal complications, indigestion,constipation, arthritis, rheumatism, sprains, muscular aches, pains, cramps, hypertension, dementia, fever, infectious dis-eases, and helminthiasis. The putative active compounds are nonvolatile pungent principles, namely gingerols, shogaols,paradols, and zingerone. These compounds are some of the extensively studied phytochemicals and account for the antioxi-dant, anti-inflammatory, antiemetic, and gastroprotective activities.A number of preclinical investigations with a wide variety of assay systems and carcinogens have shown that ginger andits compounds possess chemopreventive and antineoplastic effects. A number of mechanisms have been observed to beinvolved in the chemopreventive effects of ginger. The cancer preventive activities of ginger are supposed to be mainly dueto free radical scavenging, antioxidant pathways, alteration of gene expressions, and induction of apoptosis, all of whichcontribute towards decrease in tumor initiation, promotion, and progression. This review provides concise information frompreclinical studies with both cell culture models and relevant animal studies by focusing on the mechanisms responsible forthe chemopreventive action. The conclusion describes directions for future research to establish its activity and utility as ahuman cancer preventive and therapeutic drug. The above-mentioned mechanisms of ginger seem to be promising for cancerprevention; however, further clinical studies are warranted to assess the efficacy and safety of ginger.

Keywords Zingiber officinale, ginger, gingerols, shogaols, paradols, β-elemene, zingerone, cancer and chemoprevention

ABBREVIATIONS

DMH 1,2-dimethylhydrazine

Address correspondence to M.S. Baliga, Research and Development, FatherMuller Medical College, Father Muller Hospital Road, Kankanady, Mangalore575002, Karnataka, India Tel.: 91-824-2238331, Fax: +91-824-2437402.E-mail: [email protected]

ABTS 2, 2′-azino-bis(3-ethylbenzthiazoline-6-sulph-onic acid)

DPPH 2, 2-Diphenyl-1-PicrylhydrazylMNPB 4-(methylnitrosamino)-1-(3-pyridyl)-1-

butanone5-LO 5-lipoxygenaseDMBA 7, 12-dimethylbenz (a) anthraceneTPA 12-0-tetradecanoyl phorbol-13-acetate

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500 M.S. BALIGA ET AL.

ACF Aberrant crypt fociAP-1 Activator protein 1ARE Antioxidant response elementsApaf-1 Apoptotic protease-activating factor-1B(a)P Benzo[a]pyreneCdc2 Cell division cycle 2CIN Cervical intraepithelial neoplasiaChk2 Checkpoint kinase 2CXCR4 Chemokine receptor 4COX-1 Cyclooxygenase 1COX-2 Cyclooxygenase 1CYP p450 Cytochrome P450EGF Epidermal growth factorGSH Glutathione (γ -glutamylcysteinylglycine)GPx-1 Glutathione peroxidase-1GSR or GR Glutathione reductaseGST-P1 Glutathione S-transferase-P1GSK-3 Glycogen synthase kinase 3GADD153 Growth arrest and DNA damage-inducible

transcription factor 153(HO)-1 Heme oxygenaseH2O2 Hydrogen peroxideOH• Hydroxyl radicalIkBα IkappaBalphaiNOS Inducible NO synthaseIL-1b Interleukin-1betaJNK Jun N-terminal kinaseLTA (4) H Leukotriene A (4) hydrolaseLPS LipopolysaccharideMnSOD Manganese superoxide dismutaseMKP5 Mitogen-activated protein kinase phosphatas- 5MAPKs Mitogen-activated protein kinasesMDR1 Multi drug resistance 1MPO MyeloperoxidaseNAC N-acetylcysteineNAT N-acetyltransferaseNQO1 NAD(P)H quinone oxidoreductaseBBN N-butyl-N-(4-hydroxybutyl)-nitrosamineNO Nitric oxideMNU N-methyl-N-nitrosoureaNSAIDs Nonsteroidal anti-inflammatory drugsNSCLC Non small cell lung carcinomaNrf2 Nuclear factor-erythroid 2-related factor 2NF-kB Nuclear factor-kappaBODC Ornithine decarboxylaseONOO? PeroxynitritepAKT phosphorylated AKTPUFA Polyunsaturated fatty acidsPGE2 Prostaglandin E2PKCε Protein kinase CRNS Reactive nitrogen speciesROS Reactive oxygen speciesST SulfotransferaseO•−

2 Superoxide anion radicalTNF-α Tumor necrosis factor-alpha

UGTs UDP-glucuronosyl transferasesVEGF Vascular endothelial growth factorMIC Minimum inhibitory concentrationED Effective doseLD50 Lethal dose 50UVB Ultra Violet BAOM AzoxymethaneDSS Dextran sulfate sodiumWCRF/AICR World Cancer Research Fund/American

Institute for Cancer ResearchCYP1A1 Cytochrome P450 1A1CYP1A2 Cytochrome P450 1A2CYP1B1 Cytochrome P450 1B1CYP3A4 Cytochrome P450 3A4ERK1/2 Extracellular signal-regulated kinases 1 and 2

INTRODUCTION

Despite substantial progress in the understanding of themolecular basis, diagnosis, and treatment of cancer, it is stilla major health concern. It is the second leading cause of deathin the world after cardiac diseases. According to the recentlyavailable information, globally in the year 2002, excluding thenon-melanoma skin cancers, there were more than 10 millionnew cases of cancer recorded, with nearly 7 million cancerdeaths (WCRF/AICR, 2007). Projections are that by the year2020, these figures will increase to over 16 million new cases,with 10 million deaths, and that in 2030 there may be more than20 million new cases of cancer, with 70 per cent of cancer deathsin the low-income countries, which have minimal resources totreat the disease (WCRF/AICR, 2007).

Pioneering population-based studies by Doll and Peto (1981)showed that 75% to 80% of all cancers diagnosed could beavoided by altering lifestyle factors, such as smoking and diet.Subsequently, large numbers of experimental and population-based human studies have confirmed these observations, andalso that people in India and the other South East Asiancountries have a much lower risk of colon, gastrointestinal,prostate, breast, and other cancers than their western counter-parts (WCRF/AICR, 2007; Beliveau and Gingras, 2007). Whencompared with the Western population, the diet of Asians com-prises of copious amounts of vegetables, fruits, and spices, andis presumed to be the cause for the lower incidences of cancer(WCRF/AICR, 2007).

The dietary pattern of the people living in China, the Indiansub-continent, and South East Asia are very diverse and is de-pendent on the local culture, food availability, and the traditions.However, irrespective of this ethnic diversity and geographicallocation the people in this part of the world use plentiful amountsof ginger rhizome (Zingiber officinale) (Fig. 1) in their day today cooking and it is quite possible that the observed decrease inthe incidence of some cancers may be due to this factor (Sharmaand Clark, 1998; Altman and Marcussen, 2001).

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CHEMOPREVENTIVE EFFECTS OF GINGER AND ITS PHYTOCHEMICALS 501

Figure 1 Photograph of a ginger plant Zingiber officinale Roscoe with rhi-zome. (color figure available online)

GINGER CULTIVATION

Ginger belongs to the family Zingiberaceae and is supposedto have originated in South-East Asia (today’s Northeast India).In Sanskrit, ginger is known as Sringavera and it is speculatedthat this term may have given way to Zingiberi in Greek and thento the Latin term Zingiber (Vasala, 2004). Ginger has been culti-vated for thousands of years as a spice and also for its medicinalpurposes (Park and Pezzuto, 2002). Currently, India and Chinaare the dominant suppliers to the world market (Vasala, 2004). Itis an important cash crop in India and is grown primarily in thestates of Kerala, Karnataka, and Northeast India (Warrier, 1989;Govindarajan, 1982a; 1982b; Kemper, 1999; Vasala, 2004).

Ginger also has a long history of being cultivated in othercountries. During the medieval years, ginger plants were carriedon ships from the Indian subcontinent and were introduced todifferent parts of the world (Vasala, 2004). Ginger is also grownin other tropical countries like Nigeria, Sierra Leone, Indonesia,Bangladesh, Australia, Fiji, Jamaica, Nepal, Haiti Mexico, andHawaii (Govindarajan, 1982a; 1982b; Warrier, 1989; Sharmaand Clark, 1998; Kemper 1999; Altman and Marcussen, 2001;Vasala, 2004).

In terms of quality, Jamaican and Indian ginger are consid-ered superior followed by the West African variety. Jamaicanginger possesses delicate aroma and flavor and is sometimesconsidered as first grade. Indian ginger, known as the Cochinand Calicut ginger, has a lemon-like bynote for which somehave a preference over Jamaican ginger. Chinese ginger is lowin pungency and mainly exported as preserves in sugar syrup oras sugar candy. Nigerian and Sierra Leone dried ginger possessa camphoraceous and a coarser odor and is rich in both aromaand pungency factors (Govindarajan, 1982a; 1982b; Vasala,2004).

GINGER IN TRADITIONAL MEDICINES

Since ancient times, the rhizome of ginger has been used inGreek, Roman, Asian, Indian, Mediterranean, and Arabic sys-tems of alternative medicines (Table 1). It has been documentedto be of use in treating cold, headaches, nausea, stomach upset,diarrhea, help digestion, treat arthritis, rheumatological condi-tions, muscular discomfort, and as a carminative and antiflat-ulent (Langner et al., 1998; Kemper, 1999; Sharma and Clark,1998; Altman and Marcussen, 2001; Ali et al., 2008).

Due to its aroma and flavor, ginger was valued more for itsmedicinal properties than as an ingredient in cooking by the Ro-mans and the Greeks. The Greek physician Galen used ginger asa purificant of body and to treat conditions caused by imbalancesin body (Langner et al., 1998) (Table 1). The Africans and WestIndians also use ginger medicinally. In the United States, gingeris recommended for relieving and preventing nausea (Kemper,1999; Vasala, 2004; Warrier, 1989) (Table 1).

Ginger is an essential ingredient in many traditional Chinesemedicines and has been used since the 4th century BC. The Chi-nese considered it a tonic root for all ailments and consumed gin-ger for a wide variety of medical problems such as stomachache,diarrhoea, nausea, cholera, asthma, heart conditions, respiratorydisorders, toothache, and rheumatic complaints (Langner et al.,1998; Sharma and Clark, 1998; Kemper 1999; Altman and Mar-cussen, 2001; Ali et al., 2008) (Table 1).

Ginger has a long history of use in South East Asia, bothin dried and fresh form. In India, it has been used as medicinefrom the Vedic period and is called “maha aushadhi,” mean-ing the great medicine (Kemper, 1999; Vasala, 2004; Warrier,1989). It is an integral part of several medicinal formulationsin Ayurveda, the traditional system of Indian medicine. It isalso used in the Siddha, Unani, Srilankan, and Tibetan sys-tems of medicine and also in folk traditions and home remedies(Kemper, 1999; Vasala, 2004; Warrier, 1989). It has been rec-ommended for use as carminative, diaphoretic, antispasmodic,expectorant, peripheral circulatory stimulant, astringent, ap-petite stimulant, anti-inflammatory agent, diuretic, and diges-tive aid (Mustafa et al., 1993; Langner et al., 1998; Sharmaand Clark, 1998; Kemper 1999; Altman and Marcussen, 2001)(Table 1).

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Table 1 Traditional uses of ginger rhizome in different countries

Country Pharmacological property Reference

Arab nations Aphrodisiac, anti-emetic, stomachic, carminative; cold, headaches, nausea,stomach upset, motion sickness and morning sickness, diarrhea, help digestion,treat arthritis, rheumatological conditions, muscular discomfort, carminative,and antiflatulence.

Al-Yahya et al., 1988; Warrier, 1989; Kemper, 1999

Burma Anti-flu agent, anti-emetic, rheumatological conditions, carminative, cold, nausea,motion sickness and morning sickness and stomach upset.

Warrier, 1989; Vasala, 2004; Kemper, 1999

China Antiemetic, antitussive, expectorant, diaphoretic, antihypertensive, arthritis,rheumatological conditions, muscular discomfort, motion sickness and morningsickness, carminative and antiflatulent

Warrier, 1989; Govindarajan, 1982a, 1982b; Vasala,2004; Sharma and Clark, 1998; Altman andMarcussen, 2001

Congo Against common cold, anti-emetic, arthritis, rheumatological conditions,carminative, antiflatulent, cold, nausea and stomach upset

Warrier, 1989; Kemper, 1999

Europe Antiemetic, digestive aid, carminative, antiflatulent, cold, nausea Warrier, 1989; Kemper, 1999; Vasala, 2004Germany Antiemetic, digestive aid, preventing motion sickness Kemper, 1999; Vasala, 2004Greece Digestive aid, anti-emetic, rheumatological conditions, motion sickness and

morning sickness.Kemper, 1999; Vasala, 2004, Sharma and Clark, 1998

India Antispasmodic, antiinflammatory, antiemetic, aphrodisiac, astringent, digestiveaid, motion sickness and morning sickness. antithrombotic and antiarthritic

Warrier, 1989; Govindarajan, 1982a, 1982b; Vasala2004; Sharma and Clark, 1998

Indonesia Improving fatigue, antihypertensive, digestive aid, antirheumatic, carminative,antiflatulent, cold, nausea

Warrier, 1989; Vasala, 2004; Sharma and Clark, 1998

Japan Antiemetic, antitussive, expectorant, diaphoretic, carminative, antiflatulent, cold,nausea

Warrier, 1989; Govindarajan, 1982a; 1982b; Vasala,2004.

Srilanka Carminative, diaphoretic, antispasmodic, expectorant, peripheral circulatorystimulant, astringent, appetite stimulant, anti-inflammatory agent, diuretic anddigestive aid.

Vasala, 2004; Warrier, 1989; Langner et al., 1998;Sharma and Clark, 1998; Altman and Marcussen,2001; Kemper, 1999

Tibetan Carminative, diaphoretic, antispasmodic, expectorant, peripheral circulatorystimulant, astringent, appetite stimulant, anti-inflammatory agent, diuretic anddigestive aid.

Vasala, 2004; Warrier, 1989; Langner et al., 1998;Sharma and Clark, 1998; Altman and Marcussen,2001; Kemper, 1999

United Statesof America

Carminative, stomachic, antispasmodic, diaphoretic, against motion sickness andmorning sickness.

Warrier, 1989; Kemper, 1999; Govindarajan, 1982a;1982b; Vasala, 2004

In India ginger is also used in various kinds of traditionalcooking and estimates are that the average daily consumptionis about 8–10 grams (Murray, 1995). It is typically consumedas a fresh paste, dried powder and is an indispensable compo-nent of curry powder and sauces. In India a special tea is alsoprepared with ginger and is commonly called Masala Chai orginger tea. Recently it has also been used in some products likeginger candy, ginger bread, biscuits, pickles, and ginger flavoredcarbonated drinks (Arctangder, 1960; Bakhru, 1999).

PHARMACOLOGICAL PROPERTIES

Scientific studies have shown that ginger possesses an-timicrobial, antischistosomal, anti-inflammatory, antipyretic,antioxidative, hypoglycemic hepatoprotective, diuretic, andhypocholesterolemic effects (Chrubasik et al., 2005; Ali et al.,2008). Ginger is reported to possess myriads of benefits to thegastrointestinal tract. It increases bile secretion, prevents occur-rence of gastric ulcers, and enhances pancreatic lipase, intesti-nal lipase, disaccharidases, sucrase, and maltase activities inanimals (Chrubasik et al., 2005; Ali et al., 2008). Clinical stud-ies have also shown that ginger prevents nausea and/or emesisresulting from pregnancy, post-operation, chemotherapy, andmotion sickness, and that it can be used as a “broad-spectrumantiemetic” (Ernst and Pittler, 2000; Chaiyakunapruk, 2006; Aliet al., 2008).

CHEMISTRY OF GINGER

Phytochemical studies show that ginger rhizome containsa wide variety of biologically active compounds. The aromaand flavor of fresh ginger is different from dry ginger as someof the volatile oils are lost by evaporation during drying andchange in some chemicals (Govindarajan 1982a; 1982b; Ali etal., 2008). Quantative studies have shown that ginger rhizomecontains 3–6% fatty oil, 9% protein, 60–70% carbohydrates, 3–8% crude fiber, about 8% ash, 9–12% water, and 2–3% volatileoil (Govindarajan, 1982a; 1982b; Ali et al., 2008).

The characteristic organoleptic properties of ginger are dueto steam volatile oil and the non-volatile pungent compounds,and their concentration vary with growing conditions, tempera-ture, harvesting, and processing of the ginger rhizome (Govin-darajan 1982a; 1982b). Ginger rhizomes also contain a potentproteolytic enzyme called zingibain. In addition to the ex-tractable oleoresins, ginger also contains many vitamins andminerals (Govindarajan, 1982a; 1982b; Vasala, 2004; Ali et al.,2008).

The pleasant aroma of ginger is caused by more than 70 con-stituents present in the steam volatile oil and the active ingre-dients of ginger are supposed to be present in it (Vasala, 2004).The composition of the essential oil varies as a function of ge-ographical origin and growing conditions. However, the chiefconstituent, sesquiterpene hydrocarbons which are responsible

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for the aroma, seem to remain almost constant (Govindarajan,1982a; Vasala, 2004).

The volatile oil consists mainly of the mono- andsesquiterpenes; camphene, β-phellandrene, curcumene, cine-ole, geranyl acetate, terphineol, terpenes, borneol, geran-iol, limonene, β-elemene, zingiberol, linalool, α-zingiberene,β-sesquiphellandrene, β-bisabolene, zingiberenol and α-farmesene (Govindarajan, 1982a; 1982b). Zingiberol is the prin-cipal aroma contributing component of ginger rhizome (Ali etal., 2008). The sesquiterpene hydrocarbon α ingiberene pre-dominates and accounts for 20–30% of the oil obtained fromdry ginger (Connell and Sutherland, 1969; Yoshikawa et al.,1993).

The non-volatile pungent phytochemicals of ginger con-sists of the biologically active components, predominated bygingerols, shogaols, paradols and zingerone (Vasala, 2004)(Fig. 2). These compounds are responsible for the warm pun-gent sensation in the mouth and are also reported to accountfor many of its pharmacological effects (Govindarajan 1982a;1982b).

The quantity of [6]-gingerol in the fresh ginger rhizome wasfound to be 104–965 µg/g in common varieties of ginger avail-able in the Indian market (Nigam et al., 2009a). In fresh ginger,the gingerols, a series of chemical homologs differentiated bythe length of their unbranched alkyl chains; [3–6]-, [8]-, [10]-,and [12]-gingerols; and having a side-chain with 7–10, 12, 14, or16 carbon atoms, respectively are the major active components.Of all the gingerols, the compound 6-gingerol [5-hydroxy-1-(4-hydroxy-3-methoxy phenyl) decan-3-one is the most abundantone (Govindarajan 1982 a, b; Yoshikawa et al., 1993; Ali et al.,2008) (Fig. 2).

Gingerols are thermally labile because of the presence of a β-hydroxy keto group and readily undergo dehydration to form thecorresponding shogaols. The extent of this conversion is likelyto have a significant impact on the medicinal benefits of ginger,as the two classes of compounds vary in their bioavailability,pharmacokinetics, and pharmacological properties (Govindara-jan 1982a; 1982b; Ali et al., 2008). Shogaols may be furtherconverted to paradols by hydrogenation and are similar to gin-gerol (Govindarajan 1982a; 1982b).

The major pharmacological activity of ginger appears to bedue to gingerol and shogaol and the relative proportions of gin-gerols, shogaols, and paradols in ginger extracts are determinedby a number of factors, including the geographic origin, the ma-turity of the rhizomes at the time of harvest, and the method bywhich the extracts are prepared (Connell and Sutherland, 1969;Grzanna et al., 2005; Ali et al., 2008).

Shogaols, zingerone, and dehydrozingerone (Fig. 2), arefound only in small quantities in fresh ginger, but are presentin large amounts in stored ginger, suggesting that this conver-sion takes place during processing and storage (Connell andSutherland, 1969; Grzanna et al., 2005). The other constituentsinclude ginger protease, capsaicin, gingediol, galanolactone,gingesulfonic acid, galactosylglycerols, gingerglycolipids, di-arylheptanoids, neral, monoacyldi vitamins, and phytosterols

(Shukla and Singh, 2007; Awang, 1992; Mustafa et al., 1993;Kiuchi et al., 1982; Ali et al., 2008).

GINGER IN CANCER CHEMOPREVENTION

Chemoprevention, the term coined by Lee Wattenberg in the1970s, is a rapidly growing area of oncology. It focuses onthe prevention of cancer using synthetic or naturally occurringagents that inhibit or delay the onset of neoplasia by blockingneoplastic inception in healthy individuals who are recognizedto be at a higher risk of developing cancer and for whom a phar-macological agent can effectively inhibit the onset of cancer.Chemoprevention also plays a role in preventing the develop-ment of invasive and metastatic properties in established neo-plasms and thus differs from cancer treatment in that the goalof this approach is to lower the rate of cancer incidence (Shuklaand Pal, 2004; WCRF/AICR, 2007).

Chemoprevention can be organized into three strategies: (1)Primary prevention, preventing cancer in healthy individualswho are at high risk, for example, smokers; (2) secondary pre-vention, preventing development of cancer in individuals withprecancerous lesions like intraepithelial neoplasia, leukoplakia,dysplasia; and (3) tertiary prevention to target patients who havehad previous cancers and to prevent development of secondaryprimary tumor or recurrence (Shukla and Pal, 2004).

Studies in the past two decades have shown that ginger andsome of its constituents possess chemopreventive effects (Surhet al., 1998; Surh 1999; 2003; Shukla and Singh, 2007; Kunduet al., 2009; Park and Pezzuto, 2002; Aggarwal and Shishodia,2006).

Ginger in Skin Cancer

Incidence wise, skin cancers are the world’s leading formof cancer and a major health problem in many countries. Thebasal cell carcinoma accounts for 75%, while squamous cellcarcinoma and melanoma makes up 15% and 10% respectively.Of these, melanoma is highly metastatic and more harmful thanthe other two (WCRF/AICR, 2007). In the United States ofAmerica, more than one million new cases of basal cell andsquamous cell carcinoma are diagnosed every year, accountingfor 40% of all cancer cases (Jemal et al., 2007).

Studies in the past one decade have shown that ginger extractand some of its phytochemicals like [6]-gingerol, [6]-paradol,[6]-dehydroparadol, and zerumbone possess chemopreventiveproperties in mice (Katiyar et al., 1996; Park et al., 1998; Mu-rakami et al., 2004; Surh et al., 1999). Katiyar et al. (1996)demonstrated for the first time that the ethanolic extract of gin-ger rhizome possesses chemopreventive effects in the SEN-CAR mice. The authors observed that the topical applicationof ginger extract attenuated the tumor incidence, tumor size,number, and multiplicity induced by DMBA-initiated and pro-moted by TPA. Ginger inhibited TPA-induced epidermal ODC,

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Figure 2 Some important phytochemicals present in ginger rhizome.

cyclo oxygenase, and lipoxygenase activities and the levels ofODC mRNA expression in a dose-dependent manner. The TPA-induced epidermal edema and hyperplasia were reduced by 56%and 44%, respectively by the application of ginger extract (Kati-yar et al., 1996) (Table 2).

It is also reported that 4-, 6-, 8-, and 10-gingerols, and 6-shogaol isolated from the chloroform-soluble fraction of themethanolic extract of the dried rhizomes of ginger possess cyto-

toxic effects in the human SK-MEL-2, a human skin melanomacell line in vitro (Kim et al.,2008). The ED50 was observed tobe 8.93, 20.94, 12.12, 5.92, and 1.13 µg/ml respectively for 4-,6-, 8-, 10-gingerol and shogaol, respectively (Kim et al., 2008)(Table 2).

Studies have also shown that the topical application of 6-gingerol inhibited the DMBA-induced and TPA promoted skinpapillomagenesis, inhibited the TPA-induced inflammation,

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Table 2 Chemopreventive effects of ginger and its phytochemicals in cancers of different histological origins

Experimental Model Component Targets References

SKIN CANCERSENCAR Mice Ethanol Extract of

Ginger↓Incidence,↓ size, ↓number, ↓multiplicity in skin papillomas

(DMBA induced-TPA promoted), θ TPA induced epidermalODC, θ COX, lipoxygenase activities, θ epidermal edema, θ

hyperplasia, θ ODC mRNA expression

Katiyar et al., 1996

Skin of ICR Mice 6 Gingerol θDMBA – induced-TPA promoted Skin papillogenesis, θ

TPA-induced inflammation, θ TNFα, θ ODC, θ TPA-inducedCOX-2 expression

Park et al., 1998; Surh et al., 1999

J774.1 mousemacrophages JB6Cells

θLPS- induced Nitric Oxide Synthase, θ EGF-induced celltransformation, θ AP-1 DNA binding θ EGF-induced celltransformation, θ AP-1 DNA binding

Ippoushi et al., 2003; Bode et al., 2001;Davies et al., 2005

Human keratinocytesHaCaT cells

↓UVB-induced intracellular ROS, * caspase -3,-8,-9, * Fasexpression, θ transactivation of COX2, θ Translocation ofNF-κB, ↓IκBα phosphorylation

Kim et al., 2007

A431 cells ↑ROS, ↓Mitochondrial membrane potential, *apoptosis, ↑Bax,↓Bcl2, ↑CytC, ↑Apaf-1, *Caspase cascade

Nigam et al., 2009a

Mice Skin 6 paradol θTPA-induced inflammation, θ Ear edema, θ H2O2, θ TNFα,↓myeloperoxidase activity, ↓epidermal ODC activity, ↓UVinduced oxidized DNA Bases

Chung et al., 2001

JB-6 cells *Apoptosis,* necrosis Bode et al., 2001; Huang et al., 1996;Mouse skin two stage

carcinogenesis ICRMice

Zerumbone ↓Skin tumor incidence, ↓TPA-induced H2O2, ↓edema, ↑superoxide dismutase, ↑glutathione peroxidise 1, ↑glutathioneS transferase P1, ↑NAD(P)H quinone oxidoreductase, ↓COX2protein expression,↓ phosphorylation of extracellular signalregulated kinases, ↓leukocyte infiltration, ↓PCNA-labelling,*anti-oxidative enzymes, *phase II drug metabolizing enzymes,θ proinflammatory signalling pathways

Murakami et al., 2004

SK-MEL-2 cell lines 4-, 6-, 8-, gingerols &6 shogoal

*cytotoxicity Kim et al., 2008

ORAL CANCEROral squamous

carcinoma cell line6 & 10 paradol 3,6 &

10 dehydroparadol*Apoptosis, θ tumor promotion, *proteolytic cleavage of

procaspase3Keum et al., 2002

GASTRIC CANCERUlcerogens Ginger extract and

gingerolGastroprotective against various ulcerogens (Ethanol, NaOH, HCl

and NSAIDS)Al-Yahya et al., 1989; Yamahara et al., 1988;

Wu et al., 1990; Yoshikawa et al., 1994Halicobacter. pylori Methanolic extract, 6,

8, 10 gingerol, 6shogoal

Inhibitory effect on H. pylori including CagA+ strains Mahady et al., 2003

LUNG CANCERNSCLC cell line βelemene ↓Bcl2, ↑cleaved caspase 9, ↑poly ADP ribose polymerase,

↑release of CytC, *Caspase -3,-7 &-9 activities. G2M arrest –↓Cyclin B1, ↓Phospho cdc-2 (Tyr-161),↑ p27 (kip1),↑ phosphocdc2 (Tyr15), ↑Chk-2

Wang et al., 2005

A549 cell line 6-shogaol θcell proliferation, causes autophagic cell death and apoptosis, θ

activation of AKT,Hung et al., 2009

H-1299 human lungcancer cells

Shogaols, gingerolsdehydroginger-dione

Possess antiproliferative effects Sang et al., 2009

Female A/J Mice Zerumbone θ 4−methyl nitrosamino-1–3-pyridyl-1-butanone-induced lungtumorigenesis, θ multiplicity of lung adenomas, θ proliferation,↓NF-κB, ↓Hemeoxygenase 1 expression, *apoptosis in tumors

Kim et al., 2009

A549 cell lines 4, 6, 8 gingerol and 6shogoal


LIVER CANCERMale Wistar Rats with

hepatomaGinger extract ↓NF-κB, ↓TNFα Habib et al., 2008

p53 Mutant Mahlavucells

6 Shogoal * Apoptosis- oxidative stress mediated caspase dependentmechanism, ↑ROS, ↓intracellular glutathione, *Caspase 3/7,*DNA fragmentation, *apoptosis

Chen et al., 2007

PANCREATIC CANCERHPAC (wt)p53 &

BxPC-3(mutatedp53)

6 gingerol θCell growth (G1 arrest),*cell death, ↓Rb phosphorylation,↑p21cip1, ↓p53 levels, ↓Cyclin A, ↓cdk

Park et al., 2006

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Table 2 Chemopreventive effects of ginger and its phytochemicals in cancers of different histological origins (Continued)


BREAST CANCERSHN virgin mice Ginger extract θMammary tumors Nagasawa et al., 2002MCF-7,

MDA-MB-231cells

ACA ↓Cell viability, ↑apoptosis, ↑protein expression of caspase-3 Campbell et al., 2007

OVARIAN CANCERSKOV 3, A2780,

CaOV3, ES2 celllines

Ginger extract Selective growth inhibition of tumor cells Rhode et al., 2007

A2780 cell line 6 shogoal *cytotoxicity Rhode et al., 2007SK-OV3 cell lines 4, 6, 8, gingerol and 6

shogoal*cytotoxicity Kim et al., 2008

CERVICAL CANCERHep2 (HeLa cell line

derivative)Ginger extract *Cytotoxicity, *apoptosis, ↑superoxide production, ↓nitrate

formation, ↓glutathione, *cell shrinkage, *chromosomecondensation

Vijaya Padma et al., 2007

Balb/c mice θProgression of CIN,↓ PCNA proliferation, *apoptosis, ↓Bcl-2,↑Bax

Abdel Wahab et al., 2009b

HeLa cells Zerumbone *Cytotoxicity, *apoptosis, ↑caspase-3, *nuclear & chromatincondensation, *cell shrinkage, *multinucleation, *abnormalmitochondrial cristae, *membrane blebbing, *holes,*cytoplasmic extrusions, *apoptotic bodies

Abdel Wahab et al., 2009a

URINARY BLADDER CANCERRats Ginger extract θBBN + uracil induced urothelial lesions, ↓hyperplasia and

↓neoplasia multiplicity.Ihlaseh et al., 2006

Mice Ginger extract BBN-n-nitrosomethyl urea. No change in urea mutagenic index(DNA damage in comet assay and also in hyperplasia andtransitional cell carcinoma).

Bidinitto et al., 2006

PROSTATE CANCERDU-145, PC-3,

LNCaP, LAPC-46 gingerol ↑MKP5, θ inflammation Nonn et al., 2005

Ventral prostate ofswiss albino miceand LNCaP cells

Depolarization of mitochondrial membrane potential, ↑sub G1 cellpopulation, *DNA laddering, ↑p53, ↑Bax, *Caspase-9, -3,↓Bcl2, ↓survivin

Shukla et al., 2007

COLORECTAL CANCERLS180 cells Ginger extract Modulated expression of CYP1A2, CYP3A4, MDR1 Brandin et al., 2007YYT colon cancer

cellsGinger extract Antiproliferative activity, θ angiogenesis. Brown et al., 2008

MS1 endothelial cells 6 gingerol Anti-angiogenic activity Brown et al., 2008Male Wistar Rats Ginger extract θDMH-induced colon carcinogenesis, ↓incidence,↓ no. of tumors,

↓lipid peroxidation (TBARS & conjugated dienes), ↑SOD,↑catalase, ↑glutathione peroxidise, ↑GST, ↑glutathionereductase, ↑Vitamin C, E, and A

Manju and Nalini, 2005

Male Wistar Rats Ginger extract ↓ βGlucoronidase, ↓mucinase Manju and Nalini, 2006Rats Ethanol ginger extract θAcetic acid –induced ulceration, ? ulcerative colitis, ↓MDA,

↓PCO, ↑glutathione, ↑SOD, ↑CAT, ↓MPO, ↓TNFα, ↓PGE-2El Abher et al., 2008

Human colorectalcancer cells

6 Gingerol ↓Cell proliferation, *apoptosis, *G1 cell cycle arrest, ↓cyclin D1,*NAG1, θ β-Catenin translocation, θ cyclin D1 proteolysis.

Lee et al., 2008b

HCT-116 humancolon cancer cells

Shogaols, gingerolsdehydroginger-dione

Possess antiproliferative effects Sang et al., 2009

HCT116 colorectalcancer cells andNude Mice

6 Gingerol ↓Anchorage-dependant cancer cell growth, θ leukotriene A (4)hydrolase

Jeong et al., 2009

COLO 205 cells 6 shogoal θGrowth of human cancer cells, *apoptosis, *growth arrest, ↑ROS,↑Bax, ↑Fas, ↑FasL, ↓Bcl2, ↓Bcl-xL, *GADD 153

Pan et al., 2008

LS1747, LS180,COLO 205, COLO320 DM

Zerumbone θProliferation Murakami et al., 2002

Male ICR mice AOM - induced DSS promoted colon carcinogenesis. θ Multiplicityof colonic adenocarcinomas, ↓colon inflammation, ↓NF-κB,↓HO-1

Kim et al., 2009

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Table 2 Chemopreventive effects of ginger and its phytochemicals in cancers of different histological origins (Continued)


HCT 116 4-, 6-, 8-, gingerol and6 shogoal


Hematological MalignanciesHL-60 cells 6 gingerol, 6 paradol θCell viability, θ DNA synthesis, *apoptosis Lee et al., 1998

6 gingerol *DNA fragmentation, θ Bcl2, *H2O2,*superoxide anion Wang et al., 2003Gingerdione

derivative↑Caspase-3, ↓Bcl-2, *G1 arrest, ↑CDK, ↑p15, ↑p27, ↓cyclin D2,

↓cyclin E, ↓cdc25AHsu et al., 1998

Jurkat human T-cellleukemia cells

Galanals A and B *Apoptosis, *DNA fragmentation, *caspase-3, ↓Bcl-2, ↑Bax,alteration of mitochondrial transmembrane potential- release ofCyt C

Miyoshi et al., 2003

Symbols designates: ? = inhibit, ↓= decrease, ↑= increase and * = induce

TNF-α production, and production of ODC activity in the skinof mice (Park et al., 1998; Surh et al., 1999). Detailed studiesshowed that 6-gingerol inhibited the TPA-induced COX-2 ex-pression in mouse skin by blocking p38 MAP kinase-NF-kBsignaling pathway (Kim et al., 2004). 6-gingerol inhibited theLPS-induced generation of nitric oxide synthase (Ippoushi etal., 2003) as well as the EGF-induced cell transformation andAP-1 DNA binding in JB6 cells (Bode et al., 2001) and hu-man skin keratinocytes cell lines in a concentration dependentmanner (Davies et al., 2005) (Table 2).

Studies have shown that the topical treatment of [6]-gingerolthirty minutes before and post B(a)P treatment for 32 consec-utive weeks delayed the onset of tumorigenesis, reduced thecumulative number of tumors and decreased the tumor volume.Application of [6]-gingerol increased the sub-G1 peak in thecell cycle studies and this effect was more pronounced in thepost-treatment than in the pre-treatment group. [6]-gingerol alsoincreased the apoptosis selectively in the tumor tissues whilethis phenomenon did not occur in the corresponding non-tumortissues. [6]-gingerol treatment increased the B[a]P suppressedp53 levels and Bax with a concomitant decrease in the ex-pression of antiapoptotic proteins Bcl-2 and Survivin. Further,[6]-gingerol treatment caused release of Cytochrome c, Cas-pases activation, and concomitantly increased the Apaf-1, whichis closely involved event in apoptosis (Nigam et al., 2009a)(Table 2).

Treatment of HaCaT cells with [6]-gingerol reduced theUVB-induced intracellular reactive oxygen species levels, ac-tivation of caspase-3, -8, -9, Fas expression, transactivation ofCOX-2, and the translocation of NF-kB from cytosol to nu-cleus by suppression of IkappaBalpha phosphorylation (ser-32) (Kim et al., 2007). Pretreatment with [6]-gingerol priorto UVB irradiation (5 kJ/m2) also inhibited the induction ofCOX-2, as well as NF-kB translocation in mice skin (Kim et al.,2007).

Studies have shown that [6]-gingerol was cytotoxic to theA431 cells and mediated this effect through the generation ofROS. The increase in ROS led to decrease in mitochondrialmembrane potential and subsequently induced apoptosis. An in-crease in the Bax levels with a concomitant decrease in the levelsof Bcl-2 caused alteration of the Bax/Bcl-2 ratio. Concurrently

the levels of cytochrome-C and Apaf-1 were also increased andall these events culminated in triggering of the apoptosis by thecaspase enzymes (Nigam et al., 2009b) (Table 2).

Topical application of [6]-paradol and its synthetic non pun-gent analog, [6]-dehydroparadol, significantly, decreased theincidence and multiplicity of DMBA-initiated TPA promotedskin carcinogenesis; inhibited the TPA-induced inflammation,ear edema, H2O2 production, TNF-α production, and decreasedthe activity of MPO and epidermal ODC in mouse skin (Chunget al., 2001). Studies have also shown that [6]-paradol exerts itsinhibitory effect on cell transformation by inducing apoptosis(Bode et al., 2001) (Table 2).

Application of zerumbone before DMBA markedly sup-pressed both skin tumor incidence and the average number oftumors in the conventional 2-stage carcinogenesis model (Mu-rakami et al., 2004). Repeated treatment twice weekly duringthe post-initiation phase reduced the number of TPA-inducedtumors, decreased the TPA-induced H2O2 formation and edemaindicating its effectiveness (Murakami et al., 2004).

Biochemical studies showed that the levels of MnSOD, GPx-1, GST-P1 and NQO1were increased but not that of CYP p4501A1 or 1B1 in the epidermis. Zerumbone also decreased theTPA-induced COX-2 protein expression and phosphorylationof ERK (Murakami et al., 2004) (Table 2).

Histopathological studies clearly showed that pretreatment(s)with zerumbone suppressed leukocyte infiltration and reducedproliferating cell nuclear antigen-labeling indices (Murakami etal., 2004). These results suggest that zerumbone prevented bothtumor initiation and promotion process, through induction ofanti-oxidative and phase II drug metabolizing enzymes as well asattenuation of pro-inflammatory signaling pathways (Murakamiet al., 2004) (Table 2).

Ginger in Oral Cancer

Globally, oral cancer is one of the ten most common can-cers with nearly 90% of them being reported from the SouthEast Asia region, where the habits of tobacco chewing andsmoking are common (WCRF/AICR, 2007). Experimental stud-ies with human oral squamous carcinoma cell line (KB) have

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shown that [6]-paradol and other structurally related deriva-tives, [10]-paradol, [3]-dehydroparadol, [6]-dehydroparadol and[10]-dehydroparadol induce apoptosis in a dose-dependentmanner. The cytotoxic effects of [6]-dehydroparadol and [3]-dehydroparadol were more potent; while [10]-paradol and [10]-dehydroparadol were similar to that of [6]-paradol. Studies havealso shown that [6]-dehydroparadol caused induction of prote-olytic cleavage of pro-caspase-3 to the executor caspase-3, andthis might have been responsible for the resulting apoptosis(Keum et al., 2002) (Table 2).

Ginger and Gastric Cancer

Although ginger has been used since antiquity as medicationfor a variety of gastrointestinal disorders, there are no reportsof it being investigated for the chemopreventive effects againstgastric carcinogenesis. However several preclinical studies sug-gest its protective effects against various gastric ulcerogens (Al-Yahya et al., 1989; Yamahara et al., 1988; Wu et al., 1990;Yoshikawa et al., 1994) and also against the bacteria Helicobac-ter pylori, an important etiological agent associated with gastricand colon carcinogenesis (Yoshikawa et al., 1994; Siddaraju andDharmesh, 2007).

Studies by Mahady et al. (2003) have shown that the methanolextract of ginger, the extract fractions and the isolated con-stituents, 6-,8-,10-gingerol and 6-shogoal, inhibited the growthof the different strains of H pylori in vitro with a minimuminhibitory concentration in the range of 6.25–50 µg/ml. Thefraction containing the gingerols was the most active and effec-tively inhibited the growth of all H pylori strains with an MICrange of 0.78 to 12.5 µg/mL. There was significant activity evenagainst the more virulent CagA + strains. These results indicatethat the consumption of ginger may contribute to its chemopre-ventative effects by inhibiting the growth of the H pylori bacteria(Table 2).

The ginger free phenolic and ginger hydrolyzed phenolicfractions are also reported to possess inhibitory effects on thegrowth of H. pylori to scavenge free radicals, possess reducingpower abilities, protect DNA, and to inhibit lipid peroxidation(Siddaraju and Dharmesh, 2007). Studies have also shown that6-gingerol enhances the TRAIL-induced viability reduction byinhibiting TRAIL-induced NF-kB activation while 6-shogaolalone reduces viability by damaging microtubules in gastriccancer cells in vitro (Ishiguro et al., 2007) (Table 2).

Ginger in Lung Cancer

Worldwide lung cancer is the leading cause for cancer deathsand every year with over one million deaths and detectionof 1.2 million new cases merit urgent attention (Wang et al.,2005; WCRF/AICR, 2007). Studies have shown that β elemene,causes differential inhibitory effects on cell growth between nonsmall-cell lung carcinoma NSCLC cell lines and the normal lung

fibroblast and bronchial epithelial cell lines. β-elemene-inducesapoptosis in NSCLC through the mitochondria mediated path-way by decreasing Bcl-2 expression, increasing levels of cleavedcaspase-9 and poly (ADP-ribose) polymerase, and inducing re-lease of Cytochrome c and caspase-3, -7 and -9 activities (Wanget al., 2005).

Beta-elemene arrested NSCLC cells in G2-M phase and con-comitantly decreased the levels of cyclin B1 and phospho-Cdc2(Thr-161), increased levels of p27 (kip1) and phospho-Cdc2(Tyr-15). It also reduced the expression of Cdc25C, which de-phosphorylates/activates Cdc2, but enhanced the expression ofthe checkpoint kinase, Chk2, which phosphorylates/ inactivatesCdc25C. These findings suggest that the effect of beta-elemeneon G2-M arrest in NSCLC cells is mediated partly by a Chk2-dependent mechanism (Wang et al., 2005).

Kim et al. (2008) have observed that 4-, 6-, 8-, and 10-gingerols, and 6-shogaol isolated from the chloroform-solublefraction of the methanolic extract of the dried rhizomes of gingerto possess cytotoxic effects in the human carcinomic alveolarbasal epithelial cells A549 cells in vitro. The ED50 was observed10.42, 17.43, 9.58, 5.09, and 1.47 µg/mL respectively for 4-,6-, 8-, 10-gingerol and shogaol, respectively (Kim et al., 2008)(Table 2).

Studies by Sang et al., (2009) have also shown that [6]-paradol, [6]-, [8]-, and [10]-gingerol as well as shogaol inhib-ited the H-1299 cells. The cytotoxic effects were observed to be[10]-gingerol> [8]-gingerol>[6]-paradol>[6]-gingerol whilethat for shogaol [6]- shogaol > [8]-shogaol > [10]-shogaol andwere much stronger than the effects of [1]-dehydrogingerdione.The shogaols ([6], [8], and [10]) had much stronger growth in-hibitory effects than gingerols ([6], [8], and [10]) on H-1299 hu-man lung cancer cells. At equimolar concentrations, 6-shogaolwas more potent than 6-gingerol by nearly twenty fold (IC50 wasapproximately 8 µM for [6]-shogaol, while that for [6]-gingerolwas 150 µM). [1]-dehydrogingerdione was observed to be notas effective as the shogaols and gingerols (Sang et al., 2009).

Recently, Hung et al. (2009) have observed that 6-shogaol in-hibited cell proliferation by inducing autophagic cell death, butnot predominantly apoptosis in the human non-small cell lungcancer A549 cells. Pretreatment of cells with 3-methyladenine(3-MA), an autophagy inhibitor, suppressed 6-shogaol mediatedantiproliferation activity, suggesting that induction of autophagyby 6-shogaol is also responsible for cell death. 6-shogaol alsoinhibited the survival signaling through the AKT/mTOR signal-ing pathway by blocking the activation of AKT and downstreamtargets, including the mammalian target of rapamycin (mTOR),forkhead transcription factors (FKHR), and glycogen synthasekinase-3beta (GSK-3beta). Phosphorylation of both of mTOR’sdownstream targets, p70 ribosomal protein S6 kinase (p70S6 ki-nase) and 4E-BP1, was also diminished. Overexpression of AKTby AKT cDNA transfection decreased 6-shogaol mediated au-tophagic cell death, while its reduction potentiated 6-shogaol’seffect (Table 2).

Studies have shown that feeding of the diet mixed withZerumbone inhibited the MNPB-induced lung tumorigenesis in

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the female A/J mice. Feeding of Zerumbone at 250 and 500ppm for twenty-one consecutive days significantly inhibitedthe multiplicity of lung adenomas in a dose-dependent man-ner. Zerumbone inhibited proliferation, suppressed NF-kB, and(HO)-1 expression and induced selective apoptosis in the tu-mors, thereby consequencing the chemopreventive effects (Kimet al., 2009) (Table 2).

Ginger in Liver Cancer

Scientifically known as hepatocellular carcinoma, liver can-cer is one of the five most common cancers in the world and iscaused by chronic consumption of hepatotoxins and infectionby the hepatitis B viruses (Habib et al., 2008). Feeding of gin-ger extract to the rats subjected for hepatocellular carcinogene-sis with the hepatocarcinogen ethionine in the choline-deficientdiet, reduced the elevated expression of NF-kB and TNF-α.The authors hypothesize that ginger may act as an anti-cancerand anti-inflammatory agent by inactivating NF-kB through thesuppression of the pro-inflammatory TNF-α (Habib et al., 2008)(Table 2).

Studies have also shown that 6-shogaol induced apoptotic celldeath in the p53 mutants Mahlavu cells, a poorly differentiatedhepatoma subline highly refractory to many chemotherapeuticagents and radiotherapy. The apoptosis was observed to be me-diated through the oxidative stress-mediated caspase-dependentmechanism. The initial process involved the overproduction ofreactive oxygen species, with a concomitant depletion of in-tracellular glutathione contents. These events trigger change inmitochondrial transmembrane potential which then activates thecaspases 3/7, DNA fragmentation, and apoptosis (Chen et al.,2007) (Table 2).

Pretreatment with N-acetylcysteine (NAC) and GSH inhib-ited the process, thereby suggesting the importance of ROSin 6-shogaol-induced apoptosis. However, treatment with Boc-Asp(OMe)-fmk (a broad caspases inhibitor) and cyclosporinA (an mitochondrial permeability transition opening inhibitor)could only partially protect these cells from 6-SG-induced apop-tosis suggesting that other mechanisms could also be responsiblefor the consequent apoptosis (Chen et al., 2007) (Table 2).

Ginger in Pancreatic Cancer

Pancreatic cancer is a fatal disease with a five-year survivalrate of less than 5% due to aggressive metastasis and the refrac-tory nature of the cells to the conventional treatment regimens(WCRF/AICR, 2007). Park et al. (2006), investigated the ac-tion of [6]-gingerol on two human pancreatic cancer cell lineswith differing p53 status [HPAC expressing wild type (wt) p53and BxPC-3 expressing mutated p53]. Treatment of these cellswith [6]-gingerol inhibited the cell growth in a dose- and time-dependent manner. There was no significant difference in IC50

values between BxPC-3 cells and HPAC cells and at equivalent

concentrations the rat intestinal epithelial cells (normal cells)were resistant to the cytotoxic effects, suggesting [6]-gingerolcould afford selective advantage as a therapeutic or preventativeagent (Park et al., 2006).

The treatment with [6]-gingerol-induced cell death in bothHPAC (p53 wt) and BxPC-3 (expressing mutated p53) cells. Thestudy clearly showed that the HPAC cells are highly resistant to[6]-gingerol induced apoptosis, while the BxPC-3 was sensitive.The difference in [6]-gingerol-induced apoptosis was observedto be partly due to the altered PI3K/AKT pathways as while[6]-gingerol did not change phosphorylation of AKT protein inBxPC-3 cells, active phosphorylated AKT (pAKT) started toappear 3 hr after incubation and increased further up to 24 hr,clearly implying that [6]-gingerol-induced apoptosis in HPACcells (p53 wild type) is suppressed via the PI3K/AKT pathway(Park et al., 2006) (Table 2).

Cell cycle analysis have shown that [6]-gingerol arrested thecells in the G1-phase and at equivalent concentration (400 µM)the effect was more pronounced in the HPAC cells than in theBxPC-3 cells. Gingerol modulated the levels of various impor-tant G1 phase-regulatory proteins. In the BxPC-3, [6]-gingeroldecreased Cyclin A, Cdk 2, Cdk 4, and Cdk 6 expression andincreased the Cyclin D1 expression. While in the HPAC cells itdecreased the levels of Cyclin A and Cdk 6 expression, but itdid not affect Cdk 2 and Cdk 4. Phosphorylated Rb protein wasdecreased in both BxPC-3 and HPAC cells. [6]-gingerol alsoreduced the p53 levels of wt, but less significantly of mutant,p53-expressing cells. The expression of p21cip1 was increasedby [6]-gingerol in both BxPC-3 and HPAC cells. The treatmentof [6]-gingerol reduced the p53 level implying that the overexpression of p21cip1 by [6]-gingerol might be caused by p53-independent events in both cell lines (Park et al., 2006) (Table 2).

Ginger in Urinary Bladder Cancer

Urinary bladder cancer accounts for approximately 90% ofthe cancers of the human urinary tract. Numerous conditions aresuspected of being urinary-bladder cancer-forming agents, butonly cigarette smoking and occupational exposure to a certainclass of organic chemicals like β-naphthylamines, xenylamine,4-nirtobiphenyl, benzidine have been associated with it (Ihlasehet al., 2006).

Studies have shown that ginger prevented the BBN and uracilfeeding induced urinary bladder cancer in rats. Supplementinga diet containing 1% ginger in the post-initiation stage reducedthe multiplicity of urothelial lesions (hyperplasia and neoplasia)(Ihlaseh et al., 2006).

However, similar effects were not observed by ginger in miceinduced by BBN/ MNU. The assay endpoints clearly showedthat ginger did not alter the BBN/MNU-induced DNA damage,the incidence and multiplicity of simple and nodular hyperpla-sia, and transitional cell carcinoma suggesting that ginger ex-tract does not inhibit the development of BBN-induced mousebladder tumors (Bidinotto et al., 2006). The difference in these

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observations may be due to the disparity in the combination ofthe carcinogens used. While Ihlaseh et al. (2006) have studiedwith BBN and uracil, Bidinotto et al. (2006) have worked withBBN/MNU (Table 2).

Ginger in Colorectal Cancer

Colorectal cancer represents a major public health problemespecially in Western Europe, North America, and Australiaand accounts for over 1 million cases and about half a milliondeaths worldwide (Parkin et al., 2005). In vitro studies haveshown that ginger modulated the expression of the cytochromeP450 enzymes CYP1A2 and CYP3A4 and the transporter pro-tein MDR1 in the LS180 cells (Brandin et al., 2007). The gingerextract and 6-gingerol have been observed to possess antipro-liferative and anti-angiogenic activities in the YYT colon can-cer cells and MS1 endothelial cells, respectively (Brown et al.,2008). Further, 4-, 6-, 8-, and 10-gingerols, and 6-shogaol iso-lated from the chloroform-soluble fraction of the methanolicextract of the dried rhizomes of ginger were shown to possesscytotoxic effects in HCT-15 cell lines (Kim et al., 2008). TheED50 was observed to be 10.72, 30.05, 12.57, 6.57, and 1.76µg/ml respectively for 4-, 6-, 8-, 10-gingerol and shogaol, re-spectively (Kim et al., 2008). Recently, Sang et al. (2009) havereported that shogaols were more effective than the correspond-ing gingerols in inhibiting the cell proliferation of HCT-116human colon cancer cells.

Animal studies have shown contradictory results with gin-ger’s ability to prevent DMH-induced colon carcinogesis in rats(Manju and Nalini, 2005; Dias et al., 2006). Dias et al. (2006)observed that ginger was ineffective in preventing the DMH-induced ACF formation and did not modulate the proliferativeor apoptotic indices of the colonic crypt cells. However, the ob-servations of Manju and Nalini (2005; 2006) have been contra-dictory and these authors have observed that ginger is effectivein preventing the DMH-induced colon carcinogenesis in rats(Table 2).

The presence of phytochemicals gingerol, paradols, andshogaol and their ratios in ginger are of cardinal importancein ensuing chemopreventive effects. As these studies were per-formed in different countries (India and Brazil) it is quite pos-sible that the ratios of the phytochemicals differ and this mayhave been responsible for the divergent observations. Althougha subcutaneous injection of DMH was used as a carcinogenin these studies, the doses and the schedule followed are verydifferent. A lower dose of 20 mg/kg body weight was followedonce a week for the fifteen weeks with the Indian studies (Manjuand Nalini, 2005), while a higher dose of 40 mg/kg body weighttwice a week for two weeks was adopted in the Brazilian stud-ies (Dias et al., 2006). This may also have contributed to thecontradictory observations (Manju and Nalini, 2005; Dias et al.,2006) (Table 2).

Studies by Manju and Nalini (2005; 2006) have shown thatthe oral feeding of ginger was effective in decreasing the in-

cidence and number of tumors in the colon during both ini-tiation and post-initiation stages. Administration of ginger re-duced the lipid peroxidation (thiobarbituric acid reactive sub-stances, lipid hydroperoxides, and conjugated dienes) and in-creased the antioxidant levels of SOD, catalase, GPx, GST, GR,reduced GSH, vitamins C, E, and A concentrations. When com-pared to the carcinogen alone cohorts, studies showed that gin-ger decreased the levels of beta-glucuronidase and mucinase,and microbial enzymes important in chemical carcinogenesis(Table 2).

Feeding of ethanolic extract of ginger (100, 200, and 400mg/kg) to rats has also been observed to ameliorate the aceticacid-induced ulcerations in the colon of the rats. The protec-tive effects were better than that of sulfasalazine (500 mg/kg),the positive control at the two highest doses indicating the ef-fectiveness of ginger in preventing the ulcerative colitis. Anassociation between ulcerative colitis and an elevated risk forcolorectal cancer is well established and this observation on theprotective effects of ginger assumes significance (El-Abhar etal. (2008) (Table 2).

Treatment of human colorectal cancer cells with 6-gingerolsuppressed cell proliferation and induced apoptosis and G1 cellcycle arrest. Detailed studies showed that multiple mechanismsappear to be involved in 6-gingerol action, including proteindegradation as well as β-catenin, PKCε, and GSK-3β pathways(Lee et al., 2008b). Recently, Jeong et al. (2009), have alsoreported that [6]-Gingerol, suppressed anchorage-independentcancer cell growth by inhibiting LTA(4)H activity in HCT116colorectal cancer cells in vitro and in the nude mice, suggestingLTA(4)H to be another target for [6]-Gingerol and also that itcould be a relevant target for cancer therapy (Jeong et al., 2009)(Table 2).

Studies by Pan et al. (2008) have shown that 6- Shagol in-duced GADD153 in a time- and concentration-dependent man-ner. It also inhibited the growth of human cancer cells andinduced apoptosis in COLO 205 cells through modulation ofmitochondrial functions regulated by ROS. Pretreatment withNAC suppressed 6-shogoal-induced apoptosis thereby confirm-ing the role of ROS in the process and also that this occurs inthe early stages of apoptosis and is followed by the release ofcytochrome c, caspase activation, and DNA fragmentation. TheBax, Fas, and FasL were up-regulated, while Bcl-2 and Bcl-XLwere concomitantly down-regulated (Table 2).

Zerumbone is reported to have inhibited the proliferationof human colonic adenocarcinoma cell lines (LS174T, LS180,COLO205, and COLO320DM) in a dose-dependent manner,while the growth of normal human dermal (2F0-C25) and colon(CCD-18 Co) fibroblasts were less affected. Detailed studiesin the COLO205 cells have shown that Zerumbone inducedapoptosis suggesting its efficacy in chemoprevention of coloncancer (Murakami et al., 2002) (Table 2).

Zerumbone also prevented the AOM-induced and DSS pro-moted colon cancers in mice. Administration of Zerumboneorally at 100, 250, and 500 ppm inhibited the multiplicity ofcolonic adenocarcinomas and suppressed colonic inflammation.

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Molecular studies showed that Zerumbone suppresses mousecolon through multiple modulatory mechanisms on growth,apoptosis, inflammation, and expression of NF-kB and HO-1that are involved in colon carcinogenesis (Kim et al., 2009)(Table 2).

Ginger in Breast Cancer

Globally, excluding the nonmelanoma skin cancers inwomen, breast cancer is the second most common cancer. Itis also the second leading cause of cancer related death afterlung cancer (WCRF/AICR, 2007). Studies have shown that thechronic treatment of aqueous extract of ginger (0.125%) throughdrinking water inhibited the spontaneous mammary tumorige-nesis in mice without affecting the external appearance, bodyweight, food, water intake, and various plasma component levels(Nagasawa et al., 2002) (Table 2).

In vitro studies with 1′-acetoxychavicol acetate, a phyto-chemical of the tropical ginger showed antineoplastic and apop-togenic activities in the human breast carcinoma-derived MCF-7and MDA-MB-231 cells in vitro. At effective concentrations of10–50 µM, 1′-acetoxychavicol acetate decreased the cell via-bility in a time- and dose-dependent manner (Campbell et al.,2007). Pretreatment with the N-acetylcysteine, ascorbic acid,or trolox prevented the loss of viability suggesting that freeradical mediated cell death was ensued by 1′-acetoxychavicolacetate. Increase in apoptosis with a marked increase in the pro-tein expression of the activated form of caspase-3 was also seenin MDA-MB-231 cells suggestive of its potential use in breastcancer (Table 2).

Ginger in Ovarian Cancer

Ovarian cancer is one of the most lethal gynecologic malig-nancies and represents the fifth leading cause of cancer deathamong women in the United States of America (Rhode et al.,2007). The hydroalcoholic extract of ginger inhibited the growthof the human ovarian cancer cell lines of different chemosensi-tivity (SKOV3, A2780, CaOV3, and ES2) in a concentration (50,75, and 100 µg/mL) and time dependent (day 1, 3, and 5) man-ner in vitro. However, the untransformed human ovarian surfaceepithelial cells (HOSE) were minimally affected by ginger ex-tract indicating that the cytotoxic effect was selective only forthe neoplastic cells. Further studies with the isolated compounds(6-, 8-, and 10-gingerol as well as 6-shogaol) showed that only6-shogoal was effective in causing cytotoxicity to A2780 cellsin vitro, while the gingerols were not as effective at all timepoints (day 1, 3, 5, and 7) (Rhode et al., 2007) (Table 2).

Kim et al. (2008) have observed that 4-, 6-, 8-, and 10-gingerols, and 6-shogaol isolated from the chloroform-solublefraction of the methanolic extract of the dried rhizomes of gin-ger to possess cytotoxic effects in SKOV3 in vitro. The ED50

was observed 15.97, 15.72, 18.85, 14.52, and 11.05 µg/ml re-

spectively for 4-, 6-, 8-, 10-gingerol and shogaol respectively(Kim et al., 2008). 6-shogaol is also reported to have inhib-ited proliferation of the transgenic mouse ovarian cancer celllines, C1 (genotype: p53(-/-), c-myc, K-ras), and C2 (genotype:p53(-/-), c-myc, Akt) with ED50 values of 0.58 µM for theC1, and 10.7 µM for the C2, respectively (Kim et al., 2008)(Table 2).

Treatment with ginger resulted in significant inhibition ofIL-8 production in the ES-2 and SKOV3 cell lines, while inthe A2780 and CaOV3 the effects were not conspicuous as theendogenous production of IL-8 were negligible. Further, gingertreatment also resulted in the inhibition of VEGF secretion in allthe ovarian cell lines studied (A2780, CaOV3, ES2, and SKOV3cells) (Rhode et al., 2007). Taken together, these data showedginger and its components to be effective apoptogenic agentsand also that the extract inhibited the secretion of VEGF, aninducer of tumor angiogenesis (Table 2).

Ginger in Cervical Cancer

Cervical cancer is a major public health problem and in over-all disease burden is the second most common cancer after breastcancer (Saslow et al., 2007). The extract of ginger was evalu-ated for its chemopreventive effects on HEp-2 cell line, a cellline derived from HeLa, the human cervical cancer cell line.The extract possessed cytotoxic effect and induced apoptosisin a concentration dependent manner. Marked morphologicalchanges like in the cell shrinkage and condensation of chro-mosomes in cytological studies and DNA ladder pattern in theagarose gel electrophoresis assay were also observed. Studiesalso confirmed the involvement of free radicals as an increase inthe superoxide production; decreased nitrate formation and de-pletion of glutathione were also observed in the ginger-treatedcells (Vijaya Padma et al., 2007) (Table 2).

In vitro studies have shown Zerumbone possess cytotoxicityand induces apoptosis in the HeLa cells. The cytological ob-servations clearly showed nuclear and chromatin condensation,cell shrinkage, multinucleation, abnormalities of mitochondrialcristae, membrane blebbing, holes, cytoplasmic extrusions, andformation of apoptotic bodies. The levels of the caspase-3 werealso increased suggesting its role in mediating apoptosis (AbdelWahab et al., 2009a) (Table 2).

In vivo studies have also shown that Zerumbone halted theprogression of CIN in female Balb/c mice, treated prenatallywith diethylstilboestrol. The lowest concentration of 4 mg/kgZerumbone was not effective as there was no regression towardsproliferating CIN lesions. With increase in the dosage to 8 and16 mg/kg potent anti-proliferative effects were observed. Theeffect of the highest dose (16 mg/kg) was equal to cisplatin(10 mg/kg) used as a positive control. Zerumbone decreasedproliferation as evaluated by the quantitative levels of PCNAand concomitantly induced apoptosis via decrease in Bcl2 andconcomitant increase in the Bax (Abdel Wahab et al., 2009b)(Table 2).

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Ginger in Prostate Cancer

Studies in the past one decade indicate that prostate can-cer remains one of the most frequently diagnosed cancers inmen over the age of 50 years, especially in the West. The dis-ease is rare in Asia, Africa, and Latin America but is the mostfrequently diagnosed cancer among men in the US. African-American males have the highest incidence of prostate cancerin the world (WCRF/AICR, 2007; Nonn et al., 2007).

Prostate cancer is an attractive target for chemoprevention be-cause of its ubiquity, treatment-related morbidity, long latencybetween premalignant lesions, and clinically evident cancer, anddefined molecular pathogenesis. In vitro studies have shown that[6]-gingerol up-regulated MKP5 in both normal prostate epithe-lial cells and the neoplastic cells the DU145, PC-3, LNCaP, andLAPC-4, suggesting its utility in cancer prevention and treat-ment by preventing inflammation (Nonn et al., 2007).

Studies indicate that [6]-gingerol modulates the testosterone-induced alterations in apoptosis and related proteins in the an-drogen sensitive LNCaP cells and in the ventral prostate ofSwiss albino mice. Treatment of LNCaP cells with [6]-gingerolcaused depolarization of mitochondrial membrane potential, in-creased sub G1 cell population and DNA laddering. [6]-gingerolincreased the levels of p53 and Bax and activated caspase-9 andcaspase-3 with concomitant decrease in the Bcl-2 and survivinlevels in both LNCaP cells and in mouse ventral prostate (Shuklaet al., 2007) (Table 2).

Ginger in Hematological Malignancies

With an incidence of about 135,000 new casesestimated tohave occurred in 2007 and a prevalence of > 800,000affectedpersons in 2004 in the U.S., the hematological malignan-cies which include the various forms of leukemia, lymphoma,and myeloma are a major burden. Although all the causes ofleukaemia are not yet known, it is agreed that ionizing radia-tion, smoking, and exposure to certain chemicals are implicatedin many cases of hematological malignancy (Lichtman, 2008).

In vitro studies with human promyelocytic leukemia (HL-60) cells have shown that both [6]-gingerol and [6]-paradoldecreases the cell viability, inhibits DNA synthesis, and inducesapoptosis (Lee and Surh, 1998). 6-Gingerol causes DNA frag-mentation and inhibited Bcl-2 expression in the HL-60 cells.Mechanistic studies showed that the apoptosis could be pre-vented by catalase suggesting that 6-gingerol induced cell deathis mediated by the reactive oxygen species hydrogen peroxideand the superoxide anion (Wang et al., 2003) (Table 2).

A gingerdione derivative 1-(3, 4-dimethoxyphenyl)-3, 5-dodecenedione (I6) has also been observed to inhibit cell prolif-eration of HL-60 cells in both time- and dose-dependent man-ner. The I6-induced apoptosis was mediated by an apparentup-regulation of caspase-3, and down-regulation of antiapop-totic protein the Bcl-2. I6 also caused G1 arrest and the levelsof p15 and p27 increased, with a concomitant decrease in the

levels of cyclin D2, cyclin E, and cdc25A (Hsu et al., 2005)(Table 2).

Galanals A and B also showed potent cytotoxic effect in theJurkat human T-cell leukemia cells. Galanals induced apoptoticcell death and this was characterized by DNA fragmentationand caspase-3 activation. The anti-apoptotic Bcl-2 protein wasdown regulated while the Bax expression was enhanced. Themitochondrial damage pathway is supposed to have mediatedthe effects as galanals induced alteration in the mitochondrialtransmembrane potential and caused release of cytochrome C(Miyoshi et al., 2003) (Table 2).

MECHANISM OF ACTION

Free Radical Scavenging

Studies in the past two decades have conclusively shownthat the ROS and RNS, when produced in excess cause ox-idative stress and nitrosative stress, respectively. Among ROSand RNS, the superoxide anion radical (O•−

2 ), hydroxyl radical(OH•), nitric oxide (NO), peroxynitrite (ONOO−), and hydro-gen peroxide (H2O2) are the most important as they can causedamage to cell structures, including lipids and membranes, pro-teins, and DNA (Halliwell, 1999; 2007; Devasagayam et al.,2004).

Studies have shown that the extract of ginger and its phy-tochemicals are free radical scavengers in different cell freeassay systems (Fig. 3). The extract was observed to scavenge,superoxide, hydroxyl, nitric oxide, and ABTS*+ radicals in adose-dependent manner in vitro (Baliga et al., 2003; Jagetia etal., 2004). Ippoushi et al. (2003) have reported that [6]-gingerolexhibited antioxidant effects (Masuda et al., 2004) and causeda dose-dependent inhibition of NO production and significantreduction of iNOS in LPS-stimulated J774.1 cells (Ippoushiet al., 2003). Krishnakantha and Lokesh (1993) observed thatZingerone scavenged superoxide anion in vitro. Zingerone isalso a potent scavenger of peroxynitrite and inhibits the for-mation of peroxynitrite-mediated tyrosine nitration (Shin et al.,2005).

Dehydrozingerone has also been reported for scavengingsuperoxide radicals, hydroxyl radicals, nitric oxide, ABTS,and DPPH free radicals, and also reduced Fe (III) to Fe(II) in a cell free system (Saldanha et al., 1990; Parihar etal., 2007). 6-Gingerol and zingerone are reported to be goodscavengers of peroxyl radicals generated by pulse radioly-sis and were observed not to accelerate DNA damage in thebleomycin-Fe (III) system (Aeschbach et al., 1994). Gluco-sides of 6-gingerdiol, 5-O-beta-D-glucopyranosyl-3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decane is also a good scav-enger of free radicals (Suekawa et al., 1984).

Effect on Antioxidant Molecules

Eukaryotic cells are constantly exposed to free radicalsand have to defend themselves such that no deleterious

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Figure 3 Ginger mediates its chemopreventive Free radical scavenging, antioxidant pathways and apoptosis. [Ginger and its phytochemicals mediate chemopre-ventive effects in part by free radical scavenging, increase in antioxidant molecules the vitamin C vitamin E, β-carotene, GSH (Manju and Nalini, 2005), increasein antioxidant enzymes SOD, catalase and GPx (Ahmed et al., 2000), increase in Phase I (Sambaiah and Srinivasan, 1989; Banerjee et al., 1994) and II enzymes(Banerjee et al., 1994; Murakami et al., 2004) and by inducing cytotoxicity and apoptosis [(Surh et al., 1998; Surh 1999; 2003; Shukla and Singh, 2007; Kunduet al., 2009; Park and Pezzuto, 2002; Aggarwal and Shishodia, 2006)]. Symbols depict ↓= decrease, ↑= increase and − = inhibit. (color figure available online)

effect is incurred by the macromolecules. The cells are equippedwith the natural antioxidant molecules and the antioxidant en-zymes which protect them against the free radical-induceddamage (Halliwell, 1999; 2007; Devasagayam et al., 2004).An imbalance in antioxidant mechanisms may influence cel-lular sensitivity to free radical damage and alter suscepti-bility to disease. The natural antioxidant molecules com-prises of glutathione (GSH), thioredoxin, lipoic acid, ubiquinol,vitamin E (α–tocopherol), vitamin A (retinol), carotenoids,and vitamin C (ascorbate) (Devasagayam et al., 2004)(Fig. 3).

The water soluble vitamin C protects the cell in the aqueousregions while the fat soluble β-carotene, vitamin E is essential asa chain-breaking antioxidant and inhibitor of propagation of freeradical reactions in all cell membranes. Manju and Nalini (2005)have observed that feeding ginger increased the concentrationsof plasma vitamin C, vitamin E, and β-carotene suggesting itsefficacy in preventing the DMH-induced colon carcinogenesis.

GSH, a sulfhydryl (—SH) is one of the most highly con-centrated intracellular molecules found mainly in the cell cy-tosol and other aqueous phases of the living system. Due toits high redox potential, it is a potent antioxidant per se andalso a convenient cofactor for enzymatic reactions, requiringreducing equivalents for GST and GPx (Halliwell, 1999; 2007;Devasagayam et al., 2004).

Oral feeding of ginger as well as its oil increased the lev-els of acid-soluble sulfhydryl levels in mice and rats (Banerjeeet al., 1994; Ahmed et al., 2000; Manju and Nalini, 2005). Ad-ministration of ginger and its compound zerumbone preventedthe depletion of glutathione by the carcinogens (Murakami et al.,2004; Nakamura et al., 2004; Manju and Nalini, 2005).

Modulation of Antioxidant Enzymes

The antioxidant enzymes SOD, GPx, and catalase cooper-ate or in a synergistic method work to protect cell against ox-idative stress (Fig. 3). The SOD catalyses the dismutation ofsuperoxide radicals, a major form of ROS into hydrogen per-oxide which then gets acted upon by the GPx and catalase togive the water. When an appropriate balance exists betweenthese three enzymes, the oxidative stress is reduced and thecells are protected from the cytotoxic and mutagenic ef-fects of the ROS (Halliwell, 1999; 2007; Devasagayam et al.,2004).

Feeding ginger to rats is reported to increase the levelsof activities of the antioxidant enzymes SOD, catalase, andGPx and also that the effective dose was comparable to that ofthe ascorbic acid (Ahmed et al., 2000). Ginger restored the lev-els of these antioxidant enzymes in the colons of rat subjected toDMH-induced colon carcinogenesis (Manju and Nalini, 2005);

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acetic acid-induced ulcerative colitis (El-Abhar et al., 2008).Application of zerumbone to mice skin is also reported to haveenhanced the mRNA expression of MnSOD and GPx-1 (Mu-rakami et al., 2004).

Anti-Inflammatory Effects

Chronic inflammation results in oxidative stress and this maycontribute to the initiation and/or progression and promoting ofcancer cell growth (Philip et al., 2004; Surh and Na, 2008).Excess production of ODC, inflammatory mediators such asiNOS, a proinflammatory enzyme, are responsible for the gen-eration of NO; proinflammatory cytokines, including TNF-αand IL-1β have all been implicated in the pathogenesis of in-flammatory diseases (Philip et al., 2004; Aktan et al., 2006). Theinept stimulation of COX and the 5-LO produce prostaglandins[especially prostaglandin E(2)] and leukotrienes aids the con-version of premalignant cells to more virulent malignant forms(Philip et al., 2004; Surh and Kundu, 2005; Surh and Na,2008).

Regular administration of NSAIDs decreases the risks ofcertain cancers, thereby asserting the fact that modulation ofcellular signaling involving chronic inflammatory response byanti-inflammatory agents offers an important strategy in molec-ular target-based chemoprevention and cytoprotection (Surh andKundu, 2005; Surh and Na, 2008). However, long-term adminis-trations of NSAIDs can cause ulcerations on the gastrointestinaltract which at times can be a major clinical problem.

Ginger has been valued for its anti-inflammatory propertiesand scientific studies in the past two decades have confirmedthese findings (Grzanna et al., 2005). Ginger is a dual inhibitor ofCOX and 5-LO and this may have a better therapeutic profile as itwill have fewer side effects than non-steroidal anti-inflammatorydrugs and provides a rationale for the anti-inflammatory use ofit in chemoprevention (Grzanna et al., 2005).

Studies have shown that ginger suppresses prostaglandinsynthesis through inhibition of COX-1, COX-2, suppression ofleukotriene biosynthesis by inhibiting 5-LO, inhibit inductionof several genes involved in the inflammatory response (cy-tokines, chemokines, etc.), suppress NO production by partiallyinhibiting iNOS enzymatic activity, and reduce iNOS proteinproduction, via attenuation of NF-kB-mediated iNOS gene ex-pression (Grzanna et al., 2005; Aktan et al., 2006).

[6]-Gingerol suppressed TPA-induced epidermal ODC ac-tivity and inflammation (Park et al., 1998). At the signal trans-duction level, ginger ensues the anti-inflammatory effects by in-hibiting the phosphorylation of three mitogen-activated proteinkinases (MAPKs), extracellular signal-regulated kinases 1 and2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK),and the activation of NF-kB (Jung et al., 2009). Recently, Sanget al. (2009) have observed that 6-shogaol had much strongerinhibitory effects on arachidonic acid release and nitric oxide(NO) synthesis than 6-gingerol.

Modulation of Phase I Enzymes

Many carcinogens exert genotoxic and cytotoxic effects viabioactivation into electrophilic species, a process catalyzed pri-marily by phase I drug metabolizing enzymes, especially theCYP P450 mixed-function oxidases that ensues biotransfor-mation by oxidizing, reducing, or hydrolyzing toxins to cre-ate biotransformed intermediates (Jana and Mandlekar, 2009)(Fig. 3). At times, phase I enzymes can transform a non-toxicxenobiotic substance into a harmful toxic substance with con-comitant production of oxygen free radicals. These reactive in-termediates can induce DNA and RNA damage, and the forma-tion of protein adducts. The reactive species are often detoxifiedby phase II drug metabolizing enzymes and a properly function-ing and balanced phase II system would detoxify the metaboli-cally activated carcinogen thereby preventing mutagenesis andcarcinogenesis (Percival, 1997).

Ginger is reported to stimulate the liver microsomal cy-tochrome P450-dependent aryl hydroxylase, cytochrome P450,and cytochrome b5 (Sambaiah and Srinivasan, 1989) (Fig. 3).Studies by Banerjee et al. (1994) have shown that the oral feed-ing of the ginger oil at 10 µL/day for 14 days caused a 1.27fold increase in the levels of hepatic CYP P450 in mice (Baner-jee et al., 1994). The essential oil also inhibited the forma-tion of DNA adducts by aflatoxin B1 in vitro in a microsomalenzyme-mediated reaction possibly by affecting the microsomalenzymes (Hashim et al., 1994). The application of zerumbonewas observed to have no effect on the levels of CYP p450 1A1or 1B1 (Murakami et al., 2004).

Modulation of Phase II Enzymes

Induction of phase II drug metabolizing enzymes are one ofthe most prominent strategies for protecting cells against theelectrophilic insults induced by oxidants, stress, mutagens, car-cinogens, and carcinogenic metabolites derived from exogenousor endogenous sources (Percival 1997). This protection could beachieved through the induction of phase II detoxifying enzymessuch as GSTs, UGTs, ST, NAT, and OH-1 (Jeong et al., 2006;Jana and Mandlekar, 2009). These phase II enzymes classicallyconjugate the hydrophobic intermediates generated by the PhaseI enzymes to a water-soluble group, thus decreasing their reac-tive nature, and allowing subsequent excretion (Jana and Man-dlekar, 2009) (Fig. 3). Accordingly, the agents preferentiallyactivating phase II over phase I enzymes can be more beneficialas chemopreventive agents (Jana and Mandlekar, 2009) (Fig. 3).

At the molecular level the process is mediated mainly by theantioxidant response elements (ARE) and is mediated by theNrf2 transcription factors. Several upstream signaling pathwaysincluding mitogen-activated protein kinases, protein kinase C,phosphatidylinositol 3-kinase, and transmembrane kinase areimplicated in the regulation of Nrf2/ARE activity and many an-tioxidants derived from dietary and medicinal plants have beenfound to activate this particular redox-sensitive transcription

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factor (Jeong et al., 2009). Therefore, strategies that modulatethe levels of phase II enzymes and NRF-2 by either pharmaco-logical or nutritional means can lead to enhanced elimination ofreactive species (Jana and Mandlekar, 2009).

Banerjee et al. (1994) observed that oral feeding of ginger oilincreased the activity of aryl hydrocarbon hydroxylase and GSTin mice liver. Recently, Murakami et al. (2004) have reportedthat zerumbone enhanced the mRNA expression of GST-P1and NQO1 in the epidermis of mice. Studies with the culturednormal rat liver epithelial cells (RL34 cells) have also shownthat zerumbone increased the gene expression of several phaseII enzyme genes like GST, gamma-glutamylcysteine synthetase,GPx, and OH-1 and also that this effect was mediated throughthe Nrf2/ARE-dependent pathway (Nakamura et al., 2004).

Inhibition of Lipid Peroxidation

Lipid peroxidation is one of the most evaluated consequencesof free radicals effects on membrane structure. The polyunsat-urated fatty acids (PUFA) are vulnerable to peroxidative attackand this can cause loss of fluidity, decrease membrane potential,increased permeability for protons and calcium ions and even-tually loss of cell membranes. The lipid hydroperoxides andthe oxygenated products of lipid peroxidation can participatein the signal transduction cascade, the control of cell prolif-eration, and the induction of differentiation, maturation, andapoptosis and result in pathological and toxicological processes(Devasagayam et al., 2004). The major aldehydic end productof lipid peroxidation is malondialdehyde and is mutagenic inthe bacterial and mammalian systems of studies.

In vitro studies have shown that the ginger extract pre-vents enzymatic lipid peroxidation, cumene hydroperoxideand iron/ascorbate-induced oxidation of the membrane lipids(Shobana and Naidu, 2000; Chung et al., 2003). The antioxi-dant activity of ginger extract was retained even after boiling for30 min at 100 degrees C, indicating that the spice constituentswere resistant to thermal denaturation and suggesting that in ad-dition to imparting flavor to the food, ginger possesses potentialhealth benefits by inhibiting the lipid peroxidation (Shobana andNaidu, 2000). Ginger oil is also reported to inhibit the H2O2-induced oxidative damage to the erythrocyte and to decreaselipid peroxidation in rabbit hepatocytes (Lu et al., 2003). Feed-ing ginger also inhibited the DMH-induced increase in lipidperoxidation in the colon of rats (Manju and Nalini, 2005).

The compounds 6-gingerol and zingerone were evaluated fortheir anti-lipid peroxidative effects in different assay systems.Reports show that 6-gingerol decreased peroxidation of phos-pholipid liposomes in the presence of iron (III) and ascorbate,while, zingerone was not as effective as 6-gingerol (Aeschbachet al., 1994). Studies have also shown that zingerone waseffective in preventing the ascorbate/Fe (2+)-induced lipidperoxidation in the rat liver microsomes (Reddy and Lokesh,1992). Dehydrozingerone, the analogue of zingerone, is alsoreported to be effective in inhibiting ferrous-ion-, ferric-ion-

, and cumene-hydroperoxide-induced lipid peroxidation in ratbrain homogenates (Rajakumar and Rao, 1993). Zerumbone isalso reported to neutralize lipid peroxidation in rat hepatocytes,RL34 cells in vitro (Nakamura et al., 2004).

Inhibition of Protein Carbonyl Content

The ROS and RNS have deleterious effects on proteins andmay contribute to tissue inflammation and cell death. The aminoacids cysteine, methionine, histidine, and tryptophan residueside chains are vulnerable to attack. The oxidation of proteins(amino acids) in the active site or in the regulatory site mayaffect the activity and induce conformational changes that maylead to increased hydrophobicity and subsequent denaturation,aggregation, and precipitation (Stadtman, 1990).

Recently, El-Abhar et al. (2008) have observed that feedingof ethanolic extract (100, 200, and 400 mg/kg) of the gingerameliorated the acetic acid-induced ulcerations in the colon ofthe rats. Estimation of the protein carbonyl contents showed thatfeeding ginger extract resulted in a dose-dependent decrease inthe carbonyl content in the colons of rats treated with the ginger(El Abhar et al., 2008). Studies have also shown that [6]-gingeroleffectively suppressed the peroxynitrite-induced oxidation ofdichlorodihydrofluorescein and the formation of 3-nitrotyrosinein bovine serum albumin (BSA) and J774.1 cells (Ippoushiet al., 2003).

Ginger Possesses Cytotoxic Activities in Various Cell Lines

In an exploratory study aimed at understanding the cyto-toxic effects of certain Indian spices, Unnikrishnan and Kuttan(1988) observed that the alcoholic extracts of ginger possessedthe highest cytotoxic effects on the Dalton’s lymphoma ascitestumor cells, Chinese hamster ovary cells, Vero cells, and humanlymphocytes in vitro. The extract inhibited thymidine uptakeinto DNA and this might have affected the cell growth andproliferation.

Recently, Kim et al. (2008) have also reported that 4-, 6-, 8-,and 10-gingerols, and 6-shogaol isolated from the chloroformfraction of the methanolic extract of ginger possess cytotoxicity.Of these, 6-shogaol was observed to be most effective againsthuman A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells.

Dehydrozingerone and some of its analogues also pos-sess cytotoxic effects against KB, KB-VCR (a multidrug-resistant derivative), and A549 cell lines (Tatsuzaki et al., 2006).6-Shogaol also inhibited the proliferation of the transgenicmouse ovarian cancer cell lines, C1 (genotype: p53(-/-), c-myc,K-ras) and C2 (genotype: p53(-/-), c-myc, Akt), with a ED50

values of 0.58 µM and 10.7 µM for C1 and C2, respectively(Kim et al., 2008).

Wei et al. (2005) evaluate the cytotoxic effects of diarylhep-tanoids and gingerol-related compounds against human promye-locytic leukemia (HL-60) cells. The study showed that the

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compounds with the acetoxyl groups at 3- and/or 5-positionsof the side chain; appropriate longer alkyl side-chain length;the presence of ortho-diphenoxyl functionality on the aromaticring; and the alpha, beta-unsaturated ketone moiety in the sidechain had greater cytotoxicity.

Induction of Selective Apoptosis

Apoptosis, a form of programmed cell death, plays a fun-damental role in the maintenance of tissues and organ systemsby providing a controlled cell deletion to balanced cell prolif-eration. Studies have confirmed that many dietary chemopre-ventive agents can preferentially inhibit the growth of mutated,preneoplastic and tumor cells by targeting one or more signal-ing intermediates leading to induction of apoptosis (Sun et al.,2004; Sun, 2005; De Flora and Ferguson, 2005) (Fig. 3). Someof the pathways triggered are selective increases in free-radicalformation, endonuclease activation, induction of p53, activa-tion of caspase 3 protease, up regulation of the pro-apoptoticproteins (Bax), and down regulation of antiapoptotic proteins(Bcl-2, Bcl-XL), etc. (Hsu et al., 1998; Keum et al., 2002; Wanget al., 2003; 2005; Miyoshi et al., 2003; Park et al., 2006; Shuklaet al., 2007; Chen et al., 2007; Pan et al., 2008; Nigam et al.,2009a; 2009b; Kim et al., 2009; Abdel Wahab et al., 2009a).

With regard to ginger, Lee and Surh (1998) for the firsttime have shown that the [6]- gingerol and [6]-Paradol in-duce apoptosis in the HL-60 cells. Since then many studieswith ginger and its phytochemicals gingerol, shagol, paradol,zerumbone, galanals, β-elemene, 1-(3,4-dimethoxyphenyl)-3,5-dodecenedione, and certain diarylheptanoids have been reportedto possess apoptogenic activities (Hsu et al., 1998; Keum et al.,2002; Wang et al., 2003; 2005; Miyoshi et al., 2003; Park et al.,2006; Shukla et al., 2007; Chen et al., 2007; Pan et al., 2008;Nigam et al., 2009a; 2009b; Kim et al., 2009; Abdel Wahab etal., 2009a).

Modulation of Signal Transduction

Signal transduction pathways are recognized as potentialmolecular targets for cancer treatment and chemoprevention.Studies have shown that the cellular signaling cascades medi-ated by NF-kB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases,PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOXare targets for preventing and/or retarding cancer (Sun et al.,2004; Bode and Dong, 2004; Sun, 2005; De Flora and Fergu-son, 2005).

Studies by Frondoza et al. (2004) have shown that the gingerextract inhibits the activation of TNF-α and COX-2 expressionin human synoviocytes and that it suppresses the production ofTNF-α and PGE2. Inhibition of TNF-α and COX-2 activationwas accompanied by suppression of NF-kB and IkB-α induc-tion.

The phytochemical [6]-gingerol is reported to suppress thePMA and TPA-induced, COX-2 expression in mouse skin invivo by blocking the p38 MAP kinase-NF-kB signaling path-

way (Surh, 2002; Kim et al., 2004; 2005b). Studies by Nonnet al. (2007) have shown that [6]-gingerol inhibited the TNFα

and IL-1β-induced increase in the p38-dependent NF-kB ac-tivation and expression of pro-inflammatory genes of COX-2,IL-6, and IL-8 in normal prostatic epithelial cells. 6-Shogaol isalso shown to down regulate inflammatory iNOS and COX-2gene expression in macrophages stimulated by LPS by inhibit-ing the activation of NF-kB by interfering with the activationPI3K/Akt/I kappaB kinases IKK and MAPK (Pan et al., 2008).6-Shogaol also inhibited the lipopolysaccharide-induced dimer-ization of the Toll-like receptors (TLR4) resulting in the inhi-bition of NF-kB activation and the expression of COX-2 (Ahnet al., 2009).

Zerumbone is reported to suppress the NF-kB activationinduced by the tumor necrosis factor (TNF), okadaic acid,cigarette smoke condensate, phorbol myristate acetate, andH2O2 and that the suppression was not cell type specific. In-terestingly, α-humulene, a structural analogue of zerumbonelacking the carbonyl group, was completely inactive. Zerum-bone treatment caused suppression of the IkappaBalpha kinaseactivity, IkappaBalpha phosphorylation, IkappaBalpha degrada-tion, p65 phosphorylation, p65 nuclear translocation, and p65acylation. It also inhibited the NF-kB-dependent reporter geneexpression activated by TNF, TNFR1, TRADD, TRAF2, NIK,and IKK but not that activated by the p65 subunit of NF-kB.The NF-kB-regulated gene products, such as cyclin D1, COX-2, MMP-9, ICAM-1, c-Myc, survivin, IAP1, IAP2, XIAP, Bcl-2,Bcl-xL, Bfl-1/A1, TRAF1, and FLIP, were all down regulatedby zerumbone (Takada et al., 2005).

Modulation of Cell Cycle

The ginger constituents have been reported to inhibit thetumor cell growth through cell cycle arrest and inhibition. [6]-Gingerol inhibited the growth of the human pancreatic cancercells, the HPAC and BxPC-3 and colon cells in the G1 phase,and decreased the expression of crucial cell cycle proteins Cy-clins and Cdks (Park et al.,2006; Lee et al., 2008a). In BxPC-3,[6]-gingerol induced decrease in Cyclin A, Cdk 2, Cdk 4, andCdk 6 expression and increase in Cyclin D1 expression, whilein the HPAC cells, a decrease in the levels of Cyclin A andCdk 6 expression were prominent. [6]-Gingerol decreased thelevels of phosphorylated Rb in both BxPC-3 and HPAC cells,thereby affecting the activation of E2F which finally resulted inthe failure of cells to enter the S phase (Park et al., 2006). Inthe colon cells 6-gingerol suppressed cyclin D1 expression (Leeet al., 2008a).

Treatment of in the HL-60 cells in vitro with 1-(3,4-dimethoxyphenyl)-3,5-dodecenedione, caused cell cycle arrestin G1 by down-regulating the G1 associated cyclin D2, cyclin E,and cdc25A and up-regulation of CDKI, p15, and p27 (Hsu et al.,2005). Wang et al. (2005) observed that treatment of the non-small-cell lung cancer (NSCLC) cells with β-elemene causeda G2-M phase arrest and was accompanied by decrease in thelevels of cyclin B1 and phospho-Cdc2 (Thr-161) and increases

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in the levels of p27(kip1) and phospho-Cdc2 (Tyr-15). The G2-M arrest in NSCLC cells by β-elemene was observed to bepartly mediated by the Chk2-dependent mechanism.

Modulation of Transcription Factors

In cancer the activated aberrant signaling pathways convergeon a group of proteins known as the transcription factors. Theseproteins bind to the specific consensus sequences (cis elements)in the promoter regions of the effector genes and transacti-vate or repress the gene expression. Studies have shown thatthe transcription factors/activators like AR, Sp1, STATs, E2F,Egr1, c-Myc, HIF-1α, NF-kB, AP-1, ETS2, GLI, and p53 in theprocess of carcinogenesis and intervention (Kaur and Agarwal,2007). With respect to ginger, the active compounds gingeroland zerumbone have been reported to modulate AP-1, p53, andNF-kB.

[6]-Gingerol is reported to have inhibited the epidermalgrowth factor-induced cell transformation by inhibiting the ac-tivation of AP-1 in JB6 cells (Bode et al., 2001) and decreasethe p53 expression in the human pancreatic cancer cell lines(HPAC and BxPC-3) (Park et al., 2006). Gingerol is also shownto increase apoptosis by modulating the levels of p53 and toincrease the release of cytochrome c, activation of caspases

and Apaf–1 in mice skin subjected to BAP–induced skin tu-mors in mice (Nigam et al., 2009a). Zerumbone is also reportedto inhibit activation of NF-kB and NF-kB-regulated gene ex-pression induced by the tumor necrosis factor (TNF), okadaicacid, cigarette smoke condensate, phorbol myristate acetate, andH2O2 (Takada et al., 2005).

Ginger Affects Angiogenesis and Metastasis

Angiogenesis is a key process in the cancer metastasis (Fig.4). Recently Brown et al. (2008) have reported that the gingerextract and 6-gingerol inhibited the angiogenic potential of en-dothelial cell tubule formation in the Matrigel assays in the MS1endothelial cells. The selected ginger bioactives had an indirecteffect on MS1 endothelial cell function either by endothelialcell proliferation or by inhibiting the MS1 endothelial cell tubeformation.

Ginger reduced the secretion of VEGF in ovarian cancer cellssuggesting it may have potential in the treatment and preventionof ovarian cancer (Rhode et al., 2007). The phytochemical 6-gingerol is also reported to be highly effective in inhibitingendothelial cell tube (Brown et al., 2008).

Studies by Kim et al. (2005a) have shown that [6]-gingerol in-hibited both VEGF- and bFGF-induced proliferation and caused

Figure 4 Ginger inhibits cancer progression, angiogenesis and metastasis [Ginger extract and 6-gingerol is reported to inhibit the angiogenesis process byreducing the secretion of VEGF (Rhode et al., 2007; Brown et al., 2008). 6-gingerol also inhibited VEGF- and bFGF-induced proliferation (Kim et al., 2005a)inhibited the pulmonary metastasis (Suzuki et al., 1997) by decreasing the activities of MMP-2 or MMP-9. All these results cumulatively suggest that 6-gingerolacts as a deterrent for malignancy by selectively inhibiting angiogenesis, adhesion, invasion, motility and production of MMPs at the tumor site (Lee et al., 2008a).Zerumbone, is also reported to down-regulate the expression of CXCR4 in the HER2-overexpressing breast cancer cells which concomitantly caused inhibition ofCXCL12-induced invasion of breast and pancreatic cancer cells (Sung et al., 2008)]. (color figure available online)

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cell cycle arrest in the G1 phase, possibly by cell cycle arrest inthe G1 phase through the down regulation of cyclin D1 in thehuman endothelial cells. It also blocked capillary-like tube for-mation by endothelial cells in response to VEGF, and stronglyinhibited sprouting of endothelial cells in the rat aorta, whichaffected the formation of new blood vessels in the mouse corneain response to VEGF (Kim et al., 2005a).

Experimental studies with the malignant B16 melanomabearing mice showed for the first time that [6]-gingerol inhib-ited pulmonary metastasis (Suzuki et al., 1997) (Fig. 4). The de-crease in metastases may be partly due to its anti-angiogenic ac-tivities and stimulation of the host’s immune functions (Suzukiet al., 1997; Kim et al., 2005a). Treatment of human breastcancer MDA-MB-231 cells with increasing concentrations of[6]-gingerol caused a concentration-dependent inhibition in theadhesion, invasion, motility, and activity, with a connected de-crease in the activities of MMP-2 or MMP-9. These resultscumulatively suggest that [6]-gingerol could act as a deterrentfor the malignancy by selectively inhibiting angiogenesis, adhe-sion, invasion, motility, and production of MMPs at the tumorsite (Lee et al., 2008a).

Zerumbone is also reported to down regulate the expressionof CXCR4 in the HER2-overexpressing breast cancer cells in adose- and time-dependent manner via transcriptional regulation,inhibition of NF-kB activity, and suppression of chromatin im-munoprecipitation activity. The suppression of CXCR4 expres-sion by zerumbone also corroborated the inhibition of CXCL12-induced invasion of breast and pancreatic cancer cells, suggest-ing it to be of use as an antimetastatic agent (Sung et al., 2008).It inhibited the osteoclast formation induced by human breasttumor cells and by multiple myeloma cells.

Zerumbone decreased osteolysis in MDA-MB-231 tumor-bearing athymic mice and also blocked NF-kB ligand-inducedactivation and induction of osteoclastogenesis by the tumorcells. All these reports suggest their potential as a therapeuticagent for osteoporosis and cancer-associated bone loss (Sunget al., 2008).

Ginger Poses Immunostimulatory Effects

The immune system is an intricate network of cells and solu-ble factors released by these cells. While the B-lymphocytesproduce antibodies in response to antigenic stimulation, theT-lymphocytes induce either a humoral or cellular responsedepending on the subset of T-cells that are primed upon ini-tial contact with the antigen (Patwardhan and Gautam, 2005).Experimental studies suggest that some plants stimulate innateimmunity and, more specifically, macrophage function. Thismodulation is beneficial and may contribute towards the anti-neoplastic effects (Patwardhan and Gautam, 2005; Kraus andFranz, 1992).

Studies by Liu and Zhu (2002) have shown that the oral ad-ministration of the alcoholic extract of ginger to tumor-bearingmice significantly increased the thymus index, spleen index,percentage of phagocytosis, rate of alpha-ANAE+, and titer

of IgM. These results suggest that the alcohol extract of gin-ger improves immunologic function in tumor bearing mice andrenders beneficial effects in tumor regression (Liu and Zhu2002).

Antiemetic Property of Ginger in CancerChemotherapy-Induced Nausea and Vomiting (CINV)

Although chemotherapeutic regimens in the treatment andcontrol of cancer have improved, the chemotherapy-inducednausea and vomiting (CINV) remains a major obstacle andaffects the patient’s contentment. Ginger is an establishedantiemetic agent against various emesis-inducing agents/causesin various traditional medicinal practices. Sharma et al. (1997)for the first time have showed that administration of acetoneand hydroalcoholic extracts (50% ethanolic) were effective inpreventing 3 mg/kg cisplatin-induced emesis in healthy mon-grel dogs. The aqueous extract was observed to be ineffective,and this observation clearly suggests that the antiemetic effectof ginger was due to the non-polar constituents present in theginger rhizome. However acetone, which possessed the bestantiemetic effects, was less effective than the granisetron, a 5-HT3 receptor antagonist, used as a positive control in the study(Sharma et al., 1997).

In addition to nausea and vomiting, cisplatin also causes inhi-bition of gastric emptying. Administering ginger juice as well asthe acetone and hydroalcoholic extract of ginger to rats signifi-cantly reversed the cisplatin-induced delay in gastric emptying.The ginger juice and acetone extract were more effective thanthe 50% ethanolic extract. The reversal produced by the gingeracetone extract was similar to that caused by the 5-HT3 recep-tor antagonist ondansetron, while that by the ginger juice wassuperior to the standard drug (Sharma and Gupta, 1998).

Kawai et al. (1994) have shown that the 6, 8, and 10 shogaolsand gingerols inhibited the emesis induced by the oral admin-istration of copper sulfate pentahydrate to leopard and ranidfrogs. Diarylheptanoids and six analogues isolated from gin-ger rhizome showed inhibitory effects against copper sulphate-induced emesis in young chicks (Yang et al., 2002). Mechanisticstudies have shown that [6]-, [8]-, [10]-gingerol, and [6]-shogaolexert their anti-emetic effect at least partly by acting on the 5-HT(3) receptor ion-channel complex, probably by binding to amodulatory site distinct from the serotonin binding site. Thismay include indirect effects via receptors in the signal cascadebehind the 5-HT (3) receptor channel complex such as sub-stance P receptors and muscarinic receptors (Abdel-Aziz et al.,2006).

Studies have also shown that pretreatment with gingerol de-creased the cisplatin-induced vomiting in minks. The frequencyof cisplatin-induced retching and vomiting was significantly re-duced by gingerol and also that this effect was concentrationdependent. Cisplatin produced a significant increase in 5-HTand DA levels in the area postrema and ileum of minks, and thisincrease was inhibited by gingerol. Gingerol also suppressed theincreased immunoreactivity of substance P induced by cisplatin

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in a dose-dependent manner in the mucosa and submucosa ofileum as well as in the neurons of area postrema. All these ob-servations clearly suggest that gingerol has good activity againstcisplatin-induced emesis in minks and that this was possibly byinhibiting the central or peripheral increase of 5-HT, DA, andsubstance P (Qian et al., 2009).

However, in spite of the enthusiastic observations for itsanti-emetic properties in animals, conflicting observations havebeen reported from the limited human studies with ginger.Two studies show positive outcomes (Pace, 1987; Sontakkeet al., 2003)—one study showing no effect (Manusirivithayaet al., 2004) while another showing mixed results (Pecoraro etal., 1998). Further, recently Levine et al. (2008) have shownthat administering high protein meals with ginger reduced thedelayed nausea of chemotherapy and reduced use of antiemeticmedications.

Addition of ginger to standard antiemetic regimen has beenreported to offer no advantage in reducing nausea or vomit-ing in acute phase of cisplatin-induced emesis. In the delayedphase, ginger and metoclopramide have no statistically signifi-cant difference in efficacy (Manusirivithaya et al., 2004). Addi-tion of ginger to standard antiemetic medication did not reducethe severity of postchemotherapy nausea (Hickok et al., 2008;Zick et al., 2009). The varied results from the above studies aredifficult to assess due to the small sample size with no clearidentification or quality control or examination of the correctdose of the used ginger product (Zick et al., 2009). It is quitepossible that the opposing results observed by the investigatorsmay be due to the variations in the bioactive compounds.

CONCLUSIONS

Numerous studies in the past two decades have demon-strated unequivocally that the ginger rhizome and some of itscompounds possess chemopreventive effects against cancers ofdifferent histological origins in experimental systems. Severalmechanisms are likely to account for the observed pharmacolog-ical effects, the most important being the free radical scaveng-ing, antioxidant, antimicrobial, antimutagenic activities, anti-inflammatory increase in the antioxidant enzymes, modulationof Phase I and II enzymes, modulation of signal transduction,transcription factors and cell cycle, and induction of selectiveapoptosis in neoplastic cells (Fig. 5).

Though studies on the effects of ginger on some cancer celllines and animals substantiate its effectiveness, conflicting re-sults with chemopreventive studies on colon cancer and blad-der cancer necessitate further research, especially with authen-ticated standardized extracts before a conclusive inference isdrawn. The pharmacological activity of ginger appears to bedue to gingerol, paradols, and shogaol. The final ratio of thesecompounds in ginger are determined by a number of factors,including the geographic origin, the maturity of the rhizomes atthe time of harvest, and the method by which the extracts areprepared.

Figure 5 Molecular targets of ginger and its active principle responsible forchemoprevention [Ginger and its phytochemicals act on multiple targets to ensuechemopreventive effects like by enhancing free radical scavenging; increasingthe antioxidant molecules, antioxidant enzymes, Phase I and II enzymes, anti-inflammatory effects; inhibiting lipid peroxidation and protein carbonyl con-tent; modulating signal transduction, cell cycle proteins, transcription factors;inducing selective cytotoxicity and apoptosis of neoplastic cells; inhibiting an-giogenesis and metastasis and stimulating the immune system]. Symbols depict↓= decrease and ↑= increase. (color figure available online)

The gingerols are thermally labile and readily undergo dehy-dration to form the corresponding shogaols. The extent of thisconversion is likely to have a significant impact on the medicinalbenefits of ginger, as the two compounds vary in their bioavail-ability, pharmacokinetics, and pharmacological properties. Theopposing results observed by the authors in the colon and blad-der cancer studies as well as with human studies on antiemeticeffects against CINV may be due to the variations in the bioac-tive compounds as these studies were performed in differentcountries with non-standardized extracts. In milieu of these ob-servations it is imperative that a quality control be establishedfor the authenticity of the plant and for the presence of activephytochemicals in the required levels. The availability of au-thentic metabolite standards for quantification of the secondarymetabolite will make the scientific observations more reliableand reproducible.

Although considerable work has been done to exploit thechemopreventive effects of ginger, countless possibilities forinvestigation still remain. Further in-depth mechanistic in vitrostudies, relevant animal model studies, and rationally designedclinical trials at the normally consumed levels are sufficientfor the chemopreventive effects and also to assess for its ad-verse effects if any at higher concentrations, especially follow-ing ginger consumption over longer periods. This will also helpestablish not only whether ginger is safe and efficacious as achemopreventive agent against several human cancers, but alsoto develop and evaluate standards of evidence for health claimsfor ginger-containing foods as they become increasingly pop-ular and enter the marketplace labeled as functional foods andnutraceuticals.

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Due to its abundance, low cost, and safety in consumption,ginger remains a species with tremendous potential and count-less possibilities for further investigation. It has the potentialto develop as a non-toxic chemopreventive agent and as anantiemetic agent against chemotherapy-induced nausea, whengaps existing in knowledge are bridged. The outcomes of suchstudies may be useful for the clinical applications of gingerin humans against different cancers and may open up a newtherapeutic avenue.

ACKNOWLEDGMENTS

The authors are grateful to Rev. Fr. Patrick Rodrigus(Director), Rev. Fr. Denis D’Sa (Administrator), Dr. Sanjeev Rai(Chief of Medical Services), and Dr. Jai Prakash Alva, (Dean)of Father Muller Medical College for their unstinted support.Thanks are also due to Mr. Sabyasachi Baboo, University ofOxford, for his academic help with articles.

REFERENCES

Abdel Wahab, S.I., Abdul, A.B., Alzubairi, A.S., Mohamed Elhassan, M.,Mohan, S. (2009a). In vitro ultramorphological assessment of apoptosis in-duced by zerumbone on (HeLa). J Biomed Biotechnol. 10:769568.

Abdel Wahab, S.I., Abdul, A.B., Devi, N., Ehassan Taha, M.M., Al-Zubairi,A.S., Mohan, S., Mariod, A.A. (2009b). Regression of cervical intraepithelialneoplasia by zerumbone in female Balb/c mice prenatally exposed to diethyl-stilboestrol: Involvement of mitochondria-regulated apoptosis. Exp ToxicolPathol. 62:461–469.

Abdel-Aziz, H., Windeck, T., Ploch, M., and Verspohl, E.J. (2006). Mode ofaction of gingerols and shogaols on 5-HT3 receptors: binding studies, cationuptake by the receptor channel and contraction of isolated guinea-pig ileum.Eur J Pharmacol. 530:136–143.

Aeschbach, R., Loliger, J., Scott, B.C., Murcia, A., Butler, J., Halliwell, B., andAruoma, O.I. (1994). Antioxidant actions of thymol, carvacrol, 6-gingerol,zingerone and hydroxytyrosol. Food Chem Toxicol. 32: 31–36.

Aggarwal, B.B. and Shishodia, S. (2006). Molecular targets of dietary agentsfor prevention and therapy of cancer. Biochem Pharmacol. 7: 1397–1421.

Ahmed, R.S., Seth, V., and Banerjee, B.D. (2000). Influence of dietary ginger(Zingiber officinales Rosc) on antioxidant defense system in rat: comparisonwith ascorbic acid. Ind J Exp Biol. 38: 604–606.

Ahn, S.I., Lee, J.K., and Youn, H.S. (2009). Inhibition of homodimerization oftoll-like receptor 4 by 6-shogaol. Mol Cells. 27: 211–215.

Aktan, F., Henness, S., Tran, V.H., Duke, C.C., Roufogalis, B.D., and Ammit,A.J. (2006). Gingerol metabolite and a synthetic analogue Capsarol inhibitmacrophage NF-kappaB-mediated iNOS gene expression and enzyme activ-ity. Planta Med. 72: 727–734.

Ali, B.H., Blunden, G., Tanira, M.O., and Nemmar, A. (2008). Some phyto-chemical, pharmacological and toxicological properties of ginger (Zingiberofficinale Roscoe): A review of recent research. Food Chem Toxicol. 46:409–420.

Altman, R.D. and Marcussen, K.C. (2001). Effects of a ginger extract onknee pain in patients with osteoarthritis. Arthritis Rheum. 44: 2531–2538.

Al-Yahya, M.A., Rafatullah, S., Mossa, J.S., Ageel, A.M., Parmar, N.S., andTariq, M. (1989). Gastroprotective activity of ginger Zingiber officinale rosc,in albino rats. Am J Chin Med 17: 51–56.

Arctangder, S. (1960). Perfume and Flavour Materials of Natural Origin,Elizabeth Publisher, NJ, p. 275.

Awang, D.V.C. (1992). Ginger. Canadian Pharmaceutical Journal 125: 309–311.

Bakhru, H.K. (1999). Herbs That Heal: Natural Remedies for Good Health.Oriental Paper Backs, New Delhi, India, p. 97.

Baliga, M.S., Jagetia, G.C., Rao, S.K., and Babu, K. (2003). Evaluation of nitricoxide scavenging activity of certain spices in vitro: A preliminary study.Nahrung 47: 261–264.

Banerjee, S., Sharma, R., Kale, R.K., and Rao, A.R. (1994). Influence ofcertain essential oils on carcinogen-metabolizing enzymes and acid-solublesulfhydryls in mouse liver. Nutr Cancer. 21: 263–269.

Beliveau, R. and Gingras, D. (2007). Role of nutrition in preventing cancer. CanFam Physician. 53: 1905–1911.

Bidinotto, L.T., Spinardi-Barbisan, A.L., Rocha, N.S., Salvadori, D.M., andBarbisan, L.F. (2006). Effects of ginger (Zingiber officinale Roscoe) on DNAdamage and development of urothelial tumors in a mouse bladder carcino-genesis model. Environ Mol Mutagen. 47: 624–630.

Bode, A.M. and Dong, Z. (2004). Targeting signal transduction pathways bychemopreventive agents. Mutat Res. 555: 33–51.

Bode, A.M., Ma, W.Y., Surh, Y.J., and Dong, Z. (2001). Inhibition of epidermalgrowth factor-induced cell transformation and activator protein 1 activationby [6]-gingerol. Cancer Research. 61: 850–853.

Brandin, H., Viitanen, E., Myrberg, O., and Arvidsson, A.K. (2007). Effects ofherbal medicinal products and food supplements on induction of CYP1A2,CYP3A4, and MDR1 in the human colon carcinoma cell line LS180. Phy-tother Res. 21: 239–244.

Brown, A.C., Shah, C., Liu, J., Pham, J.T., Zhang, J,G., and Jadus, M.R. (2008).Ginger’s (Zingiber officinale Roscoe) inhibition of rat colonic adenocarci-noma cells proliferation and angiogenesis in vitro. Phytother Res. 23: 640–645.

Campbell, C.T., Prince, M., Landry, G.M., Kha, V., and Kleiner, H.E. (2007).Pro-apoptotic effects of 1′-acetoxychavicol acetate in human breast carci-noma cells. Toxicol Lett. 173:151–160.

Chaiyakunapruk, N. (2006). The efficacy of ginger for the prevention of post-operative nausea and vomiting: a meta-analysis. Am J Obstet Gynecol. 194:95–99.

Chen, C.Y., Liu, T.Z., Liu, Y.W., Tseng, W.C., Liu, R.H., Lu, F.J., Lin, Y.S.,Kuo, S.H., Chen, C.H. (2007). 6-shogaol (alkanone from ginger) inducesapoptotic cell death of human hepatoma p53 mutant Mahlavu subline viaan oxidative stress-mediated caspase-dependent mechanism. J Agric FoodChem. 55: 948–954.

Chrubasik, S., Pittler, M.H., and Roufogalis, B.D. (2005). Zingiberis rhizoma:A comprehensive review on the ginger effect and efficacy profiles. Phy-tomedicine 12: 684–701.

Chung, W.Y., Jung, Y.J., Surh, Y.J., Lee, S.S., Park, K.K. (2001). Antioxidativeand antitumor promoting effects of [6]-paradol and its homologs. Mutat Res.496: 199–206.

Chung, W.Y., Yow, C.M., and Benzie, I.F. (2003). Assessment of membrane pro-tection by traditional Chinese medicines using a flow cytometric technique:Preliminary findings. Redox Rep. 8: 31–33.

Connell, D. and Sutherland, M. (1969). A re-examination of gingerol, shogaoland zingerone, the pungent principles of ginger (Zingiber officinale Roscoe).Aus J Chem. 22: 1033–1043.

Davies, M., Robinson, M., Smith, E., Huntley, S., Prime, S., and Pa-terson, I. (2005). Induction of an epithelial to mesenchymal transitionin human immortal and malignant keratinocytes by TGF-beta1 involvesMAPK, Smad and AP-1 signalling pathways. J Cell Biochem. 95: 918–931.

De Flora, S. and Ferguson, L.R. (2005). Overview of mechanisms of cancerchemopreventive agents. Mutat Res. 591: 8–15.

Devasagayam, T.P., Tilak, J.C., Boloor, K.K., Sane, K.S., Ghaskadbi,S.S., and Lele, R.D. (2004). Free radicals and antioxidants in humanhealth: current status and future prospects. J Assoc Phys India. 52:794–804.

Dias, M.C., Spinardi-Barbisan, A.L., Rodrigues, M.A., de Camargo, J.L., Teran,E., and Barbisan, L.F. (2006). Lack of chemopreventive effects of ginger oncolon carcinogenesis induced by 1, 2-dimethylhydrazine in rats. Food ChemToxicol. 44: 877–884.

Dow

nloa

ded

by [

Uni

vers

ity o

f So

uth

Flor

ida]

at 2

0:30

22

Apr

il 20

13


Doll, R. and Peto, R. (1981). The causes of cancer: quantitative estimates ofavoidable risks of cancer in the United States today. J Natl Cancer Inst.66:1191–1308.

El-Abhar, H.S., Hammad, L.N., and Gawad, H.S. (2008). Modulating effect ofginger extract on rats with ulcerative colitis. J Ethnopharmacol. 118: 367–372.

Ernst, E. and Pittler, M.H. (2000). Efficacy of ginger for nausea and vomiting:a systematic review of randomized clinical trials. Br J Anaesth. 84: 367–371.

Frondoza, C.G., Sohrabi, A., Polotsky, A., Phan, P.V., Hungerford, D.S., andLindmark, L. (2004). An in vitro screening assay for inhibitors of proinflam-matory mediators in herbal extracts using human synoviocyte cultures. InVitro Cell Dev Biol Anim. 40: 95–101.

Govindarajan, V.S. (1982a). Ginger: Chemistry, technology, and quality evalu-ation: Part 1. Crit Rev Food Sci Nutr. 17:1–96.

Govindarajan, V.S. (1982b). Ginger: Chemistry, technology, and quality evalu-ation: Part 2. Crit Rev Food Sci Nutr. 17:189–258.

Grzanna, R., Lindmark, L., and Frondoza, C.G. (2005). Ginger: An herbalmedicinal product with broad anti-inflammatory actions. J Med Food. 8:125–132.

Habib, S.H., Makpol, S., Abdul Hamid, N.A., Das, S., Ngah, W.Z., and Yusof,Y.A. (2008). Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats. Clinics. 63: 807–813.

Halliwell, B. (1999). Antioxidant defense mechanisms: From the beginning tothe end. Free Rad Res. 31:261–272.

Halliwell, B. (2007). Biochemistry of oxidative stress. Biochem Soc Trans.35:1147–1150.

Hashim, S., Aboobaker, V.S., Madhubala, R., Bhattacharya, R.K., and Rao, A.R.(1994). Modulatory effects of essential oils from spices on the formation ofDNA adduct by aflatoxin B1 in vitro. Nutr Cancer. 21: 169–175.

Hickok, J.T., Roscoe, J.A., Morrow, G.R., and Ryan, J.L. (2007). A phaseII/III randomized, placebo-controlled, double-blind clinical trial of ginger(Zingiber officinale) for nausea caused by chemotherapy for cancer: A cur-rently accruing URCC CCOP cancer control study. Support Cancer Ther. 4:247–250.

Hsu, M.H., Kuo, S.C., Chen, C.J., Chung, J.G., Lai, Y.Y., and Huang, L.J.(2005). 1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (I6) induces G1 arrestand apoptosis in human promyelocytic leukemia HL-60 cells. Leuk Res.29:1399–1406.

Hsu, S.Y., Lin, P., Hsueh, A.J. (1998). BOD (Bcl-2-related ovarian death gene)is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable ofdimerization with diverse antiapoptotic Bcl-2 members. Mol Endocrinol. 12:1432–1440.

Hung, J.Y., Hsu, Y.L., Li, C.T., Ko, Y.C., Ni, W.C., Huang, M.S., and Kuo, P.L.(2009). 6-shogaol, an active constituent of dietary ginger, induces autophagyby inhibiting the AKT/mTOR pathway in human non-small cell lung cancerA549 cells. J Agric Food Chem. [Epub ahead of print].

Ihlaseh, S.M., de Oliveira, M.L., Teran, E., de Camargo, J.L., and Barbisan, L.F.(2006). Chemopreventive property of dietary ginger in rat urinary bladderchemical carcinogenesis. World J Urol. 24:591–596.

Ippoushi, K., Azuma, K., Ito, H., Horie, H., and Higashio, H. (2003). [6]- Gin-gerol inhibits nitric oxide synthesis in activated J774.1 mouse macrophagesand prevents peroxynitrite-induced oxidation and nitration reactions. Life Sci.73: 3427–3437.

Ishiguro, K., Ando, T., Maeda, O., Ohmiya, N., Niwa, Y., Kadomatsu, K., andGoto, H. (2007). Ginger ingredients reduce viability of gastric cancer cellsvia distinct mechanisms. Biochem Biophys Res Commun. 362: 218–223.

Jagetia, G., Baliga, M., and Venkatesh, P. (2004). Ginger (Zingiber officinaleRosc.), a dietary supplement, protects mice against radiation-induced lethal-ity: Mechanism of action. Cancer Biother Radiopharm. 19: 422–435.

Jana, S. and Mandlekar, S. (2009) Role of Phase II drug metabolizing enzymesin cancer chemoprevention. Curr Drug Metab. 10: 595–616.

Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., and Thun, M.J. (2007).Cancer statistics, 2007. CA Cancer J Clin. 57:43–66.

Jeong, C.H., Bode, A.M., Pugliese, A., Cho, Y.Y., Kim, H.G., Shim, J.H., Jeon,Y.J., Li, H., Jiang, H., and Dong, Z. (2009). [6]-Gingerol suppresses colon

cancer growth by targeting leukotriene A4 hydrolase. Cancer Res. 69: 5584–5591.

Jung, H.W., Yoon, C.H., Park, K.M., Han, H.S., and Park, Y.K. (2009). Hex-ane fraction of Zingiberis Rhizoma Crudus extract inhibits the productionof nitric oxide and proinflammatory cytokines in LPS-stimulated BV2 mi-croglial cells via the NF-kappaB pathway. Food Chem Toxicol. 47: 1190–1197.

Katiyar, S.K., Agarwal, R., and Mukhtar, H. (1996). Inhibition of tumor pro-motion in SENCAR mouse skin by ethanol extract of Zingiber officinalerhizome. Cancer Res. 56: 1023–1030.

Kaur, M. and Agarwal, R. (2007). Transcription factors: molecular targets forprostate cancer intervention by phytochemicals. Curr Cancer Drug Targets.7: 355–367.

Kawai, T., Kinoshita, K., Koyama, K., and Takahashi, K. (1994).Anti-emeticprinciples of Magnolia obovata bark and Zingiber officinale rhizome. PlantaMed. 60: 17–20.

Kemper, K.J. (1999). Ginger Longwood Herbal Task Force: www.zinopinusa.com/researchpapers/GingerScientificData.pdf (accessed Septem-ber 20th 2009)

Keum, Y.S., Kim, J., Lee, K.H., Park, K.K., Surh, Y.J., Lee, J.M., Lee, S.S.,Yoon, J.H., Joo, S.Y., Cha, I.H., and Yook, J.I. (2002). Induction of apoptosisand caspase-3 activation by chemopreventive [6]-paradol and structurallyrelated compounds in KB cells. Cancer Lett. 177: 41–47.

Kim, E.C., Min, J.K., Kim, T.Y., Lee, S.J., Yang, H.O., Han, S., Kim, Y.M., andKwon, Y.G. (2005a). [6]-Gingerol, a pungent ingredient of ginger, inhibitsangiogenesis in vitro and in vivo. Biochem Biophys Res Commun. 335: 300–308.

Kim, J.K., Kim, Y., Na, K.M., Surh, Y.J., and Kim, T.Y. (2007). [6]-Gingerolprevents UVB-induced ROS production and COX-2 expression in vitro andin vivo. Free Radic Res. 41: 603–614.

Kim, J.S., Lee, S.I., Park, H.W., Yang, J.H., Shin, T.Y., Kim, Y.C., Baek, N.I.,Kim, S.H., Choi, S.U., Kwon, B.M., Leem, K.H., Jung, M.Y., and Kim, D.K.(2008). Cytotoxic components from the dried rhizomes of Zingiber officinaleRoscoe. Arch Pharm Res. 31: 415–418.

Kim, M., Miyamoto, S., Yasui, Y., Oyama, T. Murakami, A., and Tanaka,T. (2009). Zerumbone, a tropical ginger sesquiterpene, inhibits colon andlung carcinogenesis in mice. Int J Cancer. 124: 264–271.

Kim, S.O., Chun, K.S., Kundu, J.K., and Surh, Y.J. (2004). Inhibitory effectsof [6]-gingerol on PMA-induced COX-2 expression and activation of NF-kappaB and p38 MAPK in mouse skin. Biofactors. 21: 27–31.

Kim, S.O., Kundu, J.K., Shin, Y.K., Park, J.H., Cho, M.H., Kim, T.Y., andSurh, Y.J. (2005b). [6]-Gingerol inhibits COX-2 expression by blocking theactivation of p38 MAP kinase and NF-kappaB in phorbol ester stimulatedmouse skin. Oncogene. 24: 2558–2567.

Kiuchi, F., Shibuya, M., and Sankawa, U. (1982). Inhibitors of prostaglandinbiosynthesis from ginger. Chem Pharm Bull. 30: 754–757.

Kraus, J. and Franz, G. (1992). Immunomodulating effects of polysaccharidesfrom medicinal plants. Adv Exp Med Biol. 319: 299–308.

Krishnakantha, T.P. and Lokesh B.R. (1993). Scavenging of superoxide anionsby spice principles. Ind J Biochem Biophys. 30: 133–134.

Kundu, J.K., Na, H.K., and Surh, Y.J. (2009). Ginger-derived phenolic sub-stances with cancer preventive and therapeutic potential. Forum Nutr. 61:182–192.

Langner, E., Greifenberg, S., and Gruenwald, J. (1998). Ginger: History anduse. Adv Ther. 15: 25–44.

Lee E. and Surh, Y.J. (1998). Induction of apoptosis in HL-60 cells by pungentvanilloids, [6]-gingerol and [6]-paradol. Cancer Letters. 134:163–168.

Lee, H.S., Seo E.Y., Kang N.E., and Kim W.K. (2008a). [6]-Gingerol inhibitsmetastasis of MDA-MB-231 human breast cancer cells. J Nutr Biochem. 19:313–319.

Lee, S.H., Cekanova, M., and Baek, S.J. (2008b). Multiple mechanisms areinvolved in 6-gingerol-induced cell growth arrest and apoptosis in humancolorectal cancer cells. Mol Carcinog. 47: 197–208.

Levine, M.E., Gillis, M.G., Koch, S.Y., Voss, A.C., Stern, R.M., and Koch,K.L. (2008). Protein and ginger for the treatment of chemotherapy-induceddelayed nausea. J Altern Complement Med. 14: 545–551.

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Lichtman, M.A. (2008). Battling the hematological malignancies: The 200years’ war. Oncologist. 13:126–138.

Liu, H. and Zhu, Y. (2002). Effect of alcohol extract of Zingben officinale rose onimmunologic function of mice with tumor. Wei Sheng Yan Jiu. 31:208–209.

Lu, P., Lai, B.S., Liang, P., Chen, Z.T., and Shun, S.Q. (2003). Antioxida-tion activity and protective effection of ginger oil on DNA damage in vitro.Zhongguo Zhong Yao Za Zhi. 28: 873–875.

Mahady, G.B., Pendland, S.L., Yun, G.S., Lu, Z.Z., and Stoia, A. (2003). Ginger(Zingiber officinale Roscoe) and the gingerols inhibit the growth of Cag A+strains of Helicobacter pylori. Anticancer Res. 23: 3699–3702.

Manju, V. and Nalini, N. (2005). Chemopreventive efficacy of ginger, a naturallyoccurring anticarcinogen during the initiation, post-initiation stages of 1,2dimethylhydrazine-induced colon cancer. Clin Chim Acta. 358: 60–67.

Manju, V. and Nalini, N. (2006). Effect of ginger on bacterial enzymes in 1,2-dimethylhydrazine induced experimental colon carcinogenesis. Eur J CancerPrev. 15: 377–383.

Manusirivithaya, S., Sripramote, M., Tangjitgamol, S., Sheanakul, C., Leela-hakorn, S., Thavaramara, T., and Tangcharoenpanich, K. (2004). Antiemeticeffect of ginger in gynecologic oncology patients receiving cisplatin. Int JGynecol Cancer. 14: 1063–1069.

Masuda, Y., Kikuzaki, H., Hisamoto, M., and Nakatani, N. (2004). Antioxidantproperties of gingerol related compounds from ginger. Biofactors. 21: 293–296.

Miyoshi, N., Nakamura, Y., Ueda, Y., Abed, M., Ozawa, Y., Uchida, K., andOsawa, T. (2003). Dietary ginger constituents, galanals A and B, are potentapoptosis inducers in human T lymphoma Jurkat cells. Cancer Lett. 199:113–119.

Murakami, A., Takahashi, D., Kinoshita, T., Koshimizu, K., Kim, H.W., Yoshi-hiro, A., Nakamura, Y., Jiwajinda, S., Terao, J., and Ohigashi, H. (2002).Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppressesfree radical generation, proinflammatory protein production, and cancer cellproliferation accompanied by apoptosis: The alpha,beta-unsaturated carbonylgroup is a prerequisite. Carcinogenesis. 23: 795–802.

Murakami, A., Tanaka, T., Lee, J.Y., Surh, Y.J., Kim, H.W., Kawabata, K., Naka-mura, Y., Jiwajinda, S., and Ohigashi, H. (2004). Zerumbone, a sesquiterpenein subtropical ginger, suppresses skin tumor initiation and promotion stagesin ICR mice. Int J Cancer. 110: 481–490.

Murray, M.T. (1995). The healing power of herbs: the enlightened person’sguide to the wonders of medicinal plants. Prima Publications, Rocklin, CA,Vol. 14, p. 410.

Mustafa, T., Srivastava, K.C., and Jensen, K.B. (1993). Drug DevelopmentReport (9): Pharmacology of ginger, Zingiber officinale. J Drug Dev. 6: 25–89.

Nagasawa, H., Watanabe, K., and Inatomi, H. (2002). Effects of bitter melon(Momordica charantia l.) or ginger rhizome (Zingiber offifinale rosc) onspontaneous mammary tumorigenesis in SHN mice. Am J Chinese Med. 30:195–205.

Nakamura, Y., Yoshida, C., Murakami, A., Ohigashi, H., Osawa, T., and Uchida,K. (2004). Zerumbone, a tropical ginger sesquiterpene, activates phase II drugmetabolizing enzymes. FEBS Letters. 572: 245–250.

Nigam, N., Bhui, K., Prasad, S., George, J., and Shukla, Y. (2009b). [6]-Gingerolinduces reactive oxygen species regulated mitochondrial cell death pathwayin human epidermoid carcinoma A431 cells. Chem Biol Interact. 181: 77–84.

Nigam, N., George, J., Srivastava, S., Roy, P., Bhui, K., Singh, M., and Shukla,Y. (2009a). Induction of apoptosis by [6]-gingerol associated with the modu-lation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis. Cancer Chemother Pharmacol. 65: 687–696.

Nonn, L., Duong, D., and Peehl, D.M. (2007). Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated byMAP kinase phosphatase-5 in prostate cells. Carcinogenesis 28: 1188–1196.

Pace, J. (1987). Oral ingestion of encapsulated ginger and reported self care ac-tion for the relief of chemotherapy-associated N & E. Dissertations AbstractsInternational 47: 3297–3298.

Pan, M.H., Hsieh, M.C., Kuo, J.M., Lai, C.S., Wu, H., Sang, S., and Ho, C.T.(2008). 6-Shogaol induces apoptosis in human colorectal carcinoma cells via

ROS production, caspase activation, and GADD 153 expression. Mol NutrFood Res. 52: 527–537.

Parihar, V.K., Dhawan, J., Kumar, S., Manjula, S.N., Subramanian, G., Unnikr-ishnan, M.K., and Rao, C.M. (2007). Free radical scavenging and radiopro-tective activity of dehydrozingerone against whole body gamma irradiationin Swiss albino mice. Chem Biol Interact. 170: 49–58.

Park, E.J. and Pezzuto, J.M. (2002). Botanicals in cancer chemoprevention.Cancer Met Review. 21: 231–255.

Park, K.K., Chun, K.S., Lee, J.M., Lee, S.S., and Surh, Y.J. (1998). Inhibitoryeffects of [6]-gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skintumor promotion in ICR mice. Cancer Lett. 129: 139–144.

Park, Y.J., Wen, J., Bang, S., Park, S.W., and Song, S.Y. (2006). [6]-Gingerolinduces cell cycle arrest and cell death of mutant p53-expressing pancreaticcancer cells. Yonsei Med J. 47: 688–697.

Parkin, D.M., Bray, F., Ferlay, J., and Pisani, P. (2005). Global cancer statistics2002. CA Cancer J Clinicians. 55: 74–108.

Patwardhan, B. and Gautam, M. (2005). Botanical immunodrugs: Scope andopportunities. Drug Discov Today. 10: 495–502.

Pecoraro, A., Patel, K., Guthrie, T., and Ndubisi, B. (1998). Efficacy of gin-ger as an adjunctive anti-emetic in acute chemotherapy-induced nausea andvomiting. ASHP Mid-Year Clinical Meeting, Las Vegas, NV, 1998, 33, 429E.

Percival, M. (1997). Phytonutrients and detoxification. Clinical Nutrition In-sights. 5: 1–3.

Philip, M., Rowley, D.A., and Schreiber H. (2004). Inflammation as a tumorpromoter in cancer induction. Semin Cancer Biol. 14: 433–439.

Qian, Q. H., Yue, W., Wang, Y. X., Yang, Z. H., Liu, Z. T., and Chen, W.H. (2009).Gingerol inhibits cisplatin-induced vomiting by down regulating5-hydroxytryptamine, dopamine and substance P expression in minks. ArchPharm Res. 32: 565–573.

Rajakumar, D.V. and Rao, M.N. (1993). Dehydrozingerone and isoeugenolas inhibitors of lipid peroxidation and as free radical scavengers. BiochemPharmacol. 46: 2067–2072.

Reddy, A.C. and Lokesh, B.R. (1992). Studies on spice principles as antioxidantsin the inhibition of lipid peroxidation of rat liver microsomes. Mol CellBiochem. 111:117–124.

Rhode, J., Fogoros, S., Zick, S., Wahl, H., Griffith, K.A., Huang, J., and Liu,J.R. (2007). Ginger inhibits cell growth and modulates angiogenic factors inovarian cancer cells. BMC Compl Altern Med. 7: 44.

Saldanha, L.A., Elias, G., and Rao, M.N. (1990). Oxygen radical scavenging ac-tivity of phenylbutenones and their correlation with antiinflammatory activity.Arzneimittelforschung. 40: 89–91.

Sambaiah, K. and Srinivasan, K. (1989). Influence of spices and spice principleson hepatic mixed function oxygenase system in rats. Ind J Biochem Biophys.26: 254–258.

Sang, S., Hong, J., Wu, H., Liu, J., Yang, C.S., Pan, M.H., Badmaev, V., andHo, C.T. (2009). Increased growth inhibitory effects on human cancer cellsand anti-inflammatory potency of shogaols from Zingiber officinale relativeto gingerols. J Agric Food Chem. 57:10645–10650.

Saslow, D., Castle, P.E., Cox, J.T., Davey, D.D., Einstein, M.H., and Ferris, D.G.,et al (2007). American Cancer Society Guideline for human papillomavirus(HPV) vaccine use to prevent cervical cancer and its precursors. CA CancerJ Clin. 57: 7–28.

Sharma, H. and Clark, C. (1998). Contemporary Ayurveda. Churchill Living-stone, London.

Sharma, S.S. and Gupta, Y.K. (1998). Reversal of cisplatin-induced delay ingastric emptying in rats by ginger (Zingiber officinale). J Ethnopharmacol.62: 49–55.

Sharma, S.S., Kochupillai, V., Gupta, S.K., Seth, S.D., and Gupta, Y.K. (1997).Antiemetic efficacy of ginger (Zingiber officinale) against cisplatin-inducedemesis in dogs. J Ethnopharmacol. 57: 93–96.

Shin, S.G., Kim, J.Y., Chung, H.Y., and Jeong, J.C. (2005). Zingerone as anantioxidant against peroxynitrite. J Agric Food Chem. 53: 7617–7622.

Shobana, S. and Naidu, K.A. (2000). Antioxidant activity of selected Indianspices. Prostaglandins leukotrienes and essential fatty acids. ProstaglandinsLenkot Essent Fatty Acids 62: 107–110.

Dow

nloa

ded

by [

Uni

vers

ity o

f So

uth

Flor

ida]

at 2

0:30

22

Apr

il 20

13


Shukla, Y., Pal, S.K. (2004). Dietary cancer chemoprevention: An overview. IntJ Hum Genet.4: 265–276.

Shukla, Y., Prasad, S., Tripathi, C., Singh, M., George, J., and Kalra, N.(2007). In vitro and in vivo modulation of testosterone mediated alterationsin apoptosis related proteins by [6]-gingerol. Mol Nutr Food Res. 51:1492–1502.

Shukla, Y. and Singh, M. (2007). Cancer preventive properties of ginger: A briefreview. Food Chem Toxicol. 45: 683–690.

Siddaraju, M.N. and Dharmesh, S.M. (2007). Inhibition of gastric H +, K +-ATPase and Helicobacter pylori growth by phenolic antioxidants of Zingiberofficinale. Mol Nutr Food Res. 51: 324–332.

Sontakke, S., Thawani, V., and Naik, M.S. (2003). Ginger as an antiemetic innausea and vomiting induced by chemotherapy: a randomized, cross-over,double blind study. Indian J Pharmacol. 35: 32–36.

Stadtman, E. R. (1990). Metal ion-catalyzed oxidation of proteins: biochemicalmechanism and biological consequences, Free Radic Biol Med. 9: 315–325.

Suekawa, M., Ishige, A., Yuasa, K., Sudo, K., Aburada, M., and Hosoya, E.(1984). Pharmacological studies on ginger. I. Pharmacological actions ofpungent constituents, (6)-gingerol and (6)-shogaol. J Pharmacobiodyn. 7:836–848.

Sun, S.Y. (2005). Chemopreventive agent-induced modulation of death recep-tors. Apoptosis 10: 1203–1210.

Sun, S.Y., Hail, N. Jr., and Lotan, R. (2004). Apoptosis as a novel target forcancer chemoprevention. J Natl Cancer Inst. 96: 662–672.

Sung, B., Jhurani, S., Ahn, K.S., Mastuo, Y., Yi, T., Guha, S., Liu, M., and Ag-garwal, B.B. (2008). Zerumbone down-regulates chemokine receptor CXCR4expression leading to inhibition of CXCL12-induced invasion of breast andpancreatic tumor cells. Cancer Res. 68: 8938–8944.

Surh, Y. (1999). Molecular mechanisms of chemopreventive effects of selecteddietary and medicinal phenolic substances. Mutat Res. 428: 305–327.

Surh, Y.J. (2002). Anti-tumor promoting potential of selected spice ingredientswith antioxidative and anti-inflammatory activities: A short review. FoodChem Toxicol. 40: 1091–1097.

Surh, Y.J. (2003). Cancer chemoprevention with dietary phytochemicals. NatureRev Cancer. 3: 768–780.

Surh, Y.J. and Kundu J.K. (2005). Signal transduction network leading to COX-2 induction: A road map in search of cancer chemopreventives. Arch PharmRes.28: 1–15.

Surh, Y.J. Lee, E., and Lee, J.M. (1998). Chemoprotective properties of somepungent ingredients present in red pepper and ginger. Mutat Res. 402: 259–267.

Surh, Y.J. and Na, H.K. (2008). NF-kB and Nrf2 as prime molecular targets forchemoprevention and cytoprotection with anti-inflammatory and antioxidantphytochemicals. Genes Nutr. 2: 313–317.

Surh, Y.J., Park, K.K., Chun, K.S., Lee, L.J., Lee, E., and Lee, S.S. (1999). Anti-tumor-promoting activities of selected pungent phenolic substances presentin ginger. J Env Pathol Toxicol Oncol. 18: 131–139.

Suzuki, F., Kobayashi, M., Komatsu, Y., Kato, A., and Pollard, R.B. (1997).Keishi-ka-kei-to, a traditional Chinese herbal medicine, inhibits pulmonarymetastasis of B16 melanoma. Anticancer Res. 17: 873–878.

Takada, Y., Murakami, A., and Aggarwal, B.B. (2005). Zerumbone abolishesNF-jB and IjBa kinase activation leading to suppression of antiapoptotic and

metastatic gene expression, upregulation of apoptosis, and downregulation ofinvasion. Oncogene. 24: 6957–6969.

Tatsuzaki, J., Bastow, K.F., Nakagawa-Goto, K., Nakamura, S., Itokawa, H., andLee, K.H. (2006). Dehydrozingerone, chalcone, and isoeugenol analogues asin vitro anticancer agents. J Nat Prod. 69:1445–1449.

Unnikrishnan, M.C. and Kuttan, R. (1988). Cytotoxicity of extracts of spices tocultured cells. Nutr and Cancer 11: 251–257.

Vasala, P.A. (2004). Ginger. Peter K. V., Ed., Handbook of Herbs and Spices,Vol 1. Woodhead Publishing: Cambridge, UK.

Vijaya Padma, V., Arul Diana, C. S., and Ramkuma, K.M. (2007). Induction ofapoptosis by ginger in HEp-2 cell line is mediated by reactive oxygen species.Basic Clin Pharmacol Toxicol. 100: 302–307.

Wang, C.C., Chen, L.G., and Lee, L.T., Yang, L.L. (2003). Effects of 6-gingerol,an antioxidant from ginger, on inducing apoptosis in human leukemic HL-60cells. In Vivo. 17: 641–645.

Wang, G., Li, X., Huang, F., Zhao, J., Ding, H., Cunningham, C., Coad, J.E.,Flynn, D.C., Reed, E., and Li, QQ (2005). Antitumor effect of beta-elemenein non-small-cell lung cancer cells is mediated via induction of cell cyclearrest and apoptotic cell death. Cell Mol Life Sci. 62: 881–893.

Warrier, P.K. (1989). Spices in Ayurveda. In: Strategies for Export Developmentof Spices, p. 28. George, C.K., Sivadasan, C.R., Devakaran, D., Sreekumari,K.P., Eds., Spices Board, Cochin and International Trade Centre, Geneva.

WCRF/ AICR (2007). World Cancer Research Fund / American Institute forCancer Research. Food, Nutrition, Physical Activity, and the Prevention ofCancer: A Global Perspective. AICR, Washington DC.

Wei, Q.Y., Ma, J.P., Cai, Y.J., Yang, L., and Liu, Z.L. (2005). Cytotoxic andapoptotic activities of diarylheptanoids and gingerol-related compounds fromthe rhizome of Chinese ginger. J Ethnopharmacol. 102: 177–184.

Wu, H., Ye, D., Bai, Y., and Zhao, Y. (1990). Effect of dry ginger and roastedginger on experimental gastric ulcers in rats. Zhongguo Zhong Yao Za Zhi.(In Chinese) 15: 278–280.

Yamahara, J., Mochizuki, M., Rong, H.Q., Matsuda, H., and Fujimura, H.(1988). The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol.23: 299–304.

Yang, Y., Kinoshita, K., Koyama, K., Takahashi, K., Kondo, S., and Watanabe,K. (2002). Structure-antiemetic-activity of some diarylheptanoids and theiranalogues. Phytomedicine 9:146–152.

Yoshikawa, M., Hatakeyama, S., Chatani, N., Nishino, Y., and Yamahara, J.(1993). Qualitative and quantitative analysis of bioactive principles in Zin-giberis Rhizoma by means of high performance liquid chromatography andgas liquid chromatography. On the evaluation of Zingiberis Rhizoma andchemical change of constituents during Zingiberis Rhizoma processing. Yaku-gaku Zasshi. 113: 307–315.

Yoshikawa, M., Yamaguchi, S., Kunimi, K., Matsuda, H., Okuno, Y., Yama-hara, J., and Murakami, N. (1994). Stomachic principles in ginger. III. Ananti-ulcer principle, 6-gingesulfonic acid, and three monoacyldigalactosyl-glycerols, gingerglycolipids A, B, and C, from Zingiberis Rhizoma originat-ing in Taiwan. Chem Pharmacol Bull.42: 1226–1230.

Zick, S.M., Ruffin, M.T., Lee, J., Normolle, D.P., Siden, R., Alrawi, S., andBrenner, D.E. (2009). Phase II trial of encapsulated ginger as a treatmentfor chemotherapy-induced nausea and vomiting. Support Care Cancer 17:563–572.

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Update on the Chemopreventive Effects of Ginger and its Phytochemicals

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