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Review ArticleHuman Interferon Alpha-2b: A Therapeutic Protein forCancer Treatment

Ratih Asmana Ningrum

Research Center for Biotechnology, Cibinong Science Center, Jalan Raya Bogor km , Cibinong, Bogor, West Java , Indonesia

Correspondence should be addressed to Ratih Asmana Ningrum; [email protected]

Received January ; Accepted January ; Published March

Academic Editors: A. Asai and A. Espinosa

Copyright Ratih Asmana Ningrum. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Human intereron alpha (hIFN) is a wide biological activity cytokine that is used in hepatitis and cancer treatments. It regulatesmany genes that are involved in antiviral and antiprolierative activities. Tis mini review ocuses on human intereron alpha-b(hIFN-b) as therapeutic protein or cancer treatment. Te review covers hIFN-b molecular characteristic and its molecularmechanism by Janus activated kinase/signal transducer activation o transcription (JAK-SA) pathway. Te JAK-SA pathwayregulates not onlyproteins involvedin inhibitiono prolieration but also apoptosis. As additional discussiono clinical applications,the use o recombinant hIFN-b (rhIFN-b) as therapeutic protein in several types o cancer is also explained.

1. Introduction

Cancer is a rst cause o death in developed countries and thesecondcause o death in developing countries. It wasreportedthat approximately . million cancer cases occur worldwidewith . million o mortality rate. About % o deathsarise in developing countries. Breast cancer in women andlung cancer in men are the biggest cause o death, ollowedby stomach, liver, cervix, and prostate cancers. Cancer is adisease caused by uncontrolled cell growth. Growth o thesecells causes damage to surrounding tissues and spreads toother tissues via the blood or lymphatic circulation [,].

Cancer is generally derived rom one cell with accu-mulated changes in several different genes. Mutation canbe caused by exposure to carcinogens, radiation, or inec-tion by bacteria and viruses. Accumulation o mutationscausing abnormal cell growth is known as premalignancy.Genes that are involved in cancer are divided into twocategories: oncogene and tumor suppressor. Protooncogenesareprotein-coding genesthat promote cell division, includinggrowth actors (e.g., platelet-derived growth actor, epidermalgrowth actor, and broblast growth actor), growth actorreceptors (e.g., HER ERBB, ERBB, and IGF-R), andproteins in signal transduction pathways (e.g., RAS, ABL, andRAF). Oncogenes are the mutated orms o protooncogenes.

Mutation in oncogenes causes different characteristics oroverexpression o protein that triggers the growth o abnor-mal cells. umor suppressor genes are protein-coding genesthat suppress cell division, such as RB and p. Mutations intumor suppressor lead to loss o suppressor activity so that thecells become abnormal in growth. Abnormal cells are used asa therapeutic targets or cancer treatment [,].

Cancer treatment can be perormed in various ways,such as surgery, chemotherapy, radiotherapy, immunother-apy, gene therapy, or protein therapy. Recombinant thera-peutic proteins that have been widely used in cancer are

enzymes (Elspar, Oncaspar, and Elitek), toxins (denileukindifitox or ontak), monoclonal antibodies (Zevalin, Mylotarg,Bexxar, Herceptin, Avastin, Erbitux, Rituxan, Vectibix, andCampath), and cytokines (interleukin-, intereron-n,intereron-, and intereron-b). rhIFN-b was rstapproved as therapeutic protein by United States Food andDrug Administration (FDA) in . It is used or thetreatment o hairy cell leukemia and currently as much as countries have been using rhIFN-b in hepatitis andcancer treatments [, ]. rhIFN-b is widely applied inmonotherapy or in combination therapy with other drugs.rhIFNb is combined with ribavirin, lamivudine, or ade-

vor on hepatitis treatment and combined with cytarabin,

Hindawi Publishing CorporationScientificaVolume 2014, Article ID 970315, 8 pageshttp://dx.doi.org/10.1155/2014/970315
http://dx.doi.org/10.1155/2014/970315http://dx.doi.org/10.1155/2014/970315


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vinblastine, -uorouracil, tamoxien, or interleukin- oncancer treatment [].

2. Molecular Characteristics of hIFN-2b

Te intererons (IFNs) were rst introduced in as

antiviral molecules. Based on their receptor types on the cellmembrane surace, IFNs are classied into type I and type II.ype I consists o IFN, IFN, IFN, andIFN, while type IIconsists o IFN. IFN type I is a amily o cytokines in whichamino acid sequence similarity reaches %. Receptorsthat are recognized by the type I are grouped into twosubunits, IFNAR- and IFNAR-. IFNAR- consists o threetypes, namely, IFNAR-a, IFNAR-b, and IFNAR-c, respec-tively. IFNAR-chas important role in ligandbinding and sig-nal transduction, whereas IFNAR-a and IFNAR-b are com-petitive inhibitors that prevent IFN rom binding to IFNAR-c. IFN has wide biological activities ranging as antiprolier-ation, immunomodulation, and antiviral. IFNcoding genes

are located on human chromosome number . Tey have nointrons andencodepolypeptide chain o - amino acids.Some IFNs are unglycosylated but some are glycosylatedproteins with different degrees o glycosylation [].

hIFN-b molecule is a glycoprotein consisting o amino acids with O-glycosylated threonine at position .wo disulde bonds are ormed by cysteines at position and as well as and (Figure ). Bond ormed bypositions and is notrequired in biological activity. Aminoacid residues that are important in the biological activity areLeu, Lys, Arg, His, Phe, Arg, Lys, Gln,yr, yr, Lys, Glu, Arg, and Glu. Basedon crystal structure that is mediated by zinc dimer, each

monomer o rhIFN-b consists o ve alpha helices (calledhelix A to E) that are connected by a loop AB, BC, CD, andDE. Residues that are important in the structural integrityare Phe, yr, and yr. Residues that are importantin receptor binding are the AB loop (Arg, Leu, Phe,Leu, Lys, Arg, and His), helix B (Ser), helix C(Tr, Lys, yr, and yr), D helix (Arg, lys,Gln, Lys, andGlu), andhelix E (Arg andGlu).Figureshows a structure o rhIFN-b [,,].

3. Molecular Mechanism of hIFN-2bas Anticancer

Antiprolierative activity o hIFN- consists o direct andindirect activities. Direct activity occurs through cancer cellgrowth inhibition by cell cycle arrest, apoptosis, or differenti-ation. Indirect activity occurs through activation o immunecells such as cells and natural killer cells, inhibition o vas-cularization (antiangiogenesis), and induction o cytokines.Te antiprolierative activity is the result o gene expressionregulation. It is initiated by signal transduction pathwaysand transcriptional activation o JAK-SA. Study o geneexpression in melanoma cell lines (WM), brosarcoma(H), embryonic broblasts, and human dendritic cellsreported that hIFNs regulate more than genes o signaltransduction pathways in cells [,].

C1 C98

C29 C138

F : Molecular structure o hIFNb (by PyMOL).

JAK-SA pathway is initiated by receptors bindingon the cell surace. JAK, a tyrosine kinase enzyme, canactivate SA through tyrosine phosphorylation (Figure).SA amily consists o seven proteins, namely, SA-,SA-, SA-, SA-, SA-a, SA-b, and SA-,respectively and JAK amily consists o our proteins, namely,JAK-, JAK-, JAK-, and tyrosine kinase- (YK-). JAK-and YK- that are activated by IFN will result in phospho-rylation and dimerization. SA protein- (P) and SA- (p) subsequently translocated with intereron regulatingactor- (IRF- or P) to the cell nucleus. Te proteincomplex known as IFN-stimulated gene actor (ISGF-)can activate intereron stimulating response element (ISRE).wo phosphorylated subunits o Stat orm alpha activationactor that binds to gamma activation sequence (GAS). Teseinduce transcription o hundreds o intereron-stimulatedgenes (ISGs) that are involved in antiprolierative as well asantiviral activity [,,,].

Mechanism o action o hIFNb in inuencing thegrowth o various cancer cells occurs via the JAK-SA signaltransduction. JAK-SA pathway related to the MAPK path-way as a major pathway in cell prolieration. MAPK pathwayound in all eukaryotic cells and used to control a varietyo processes in the cell, such as prolieration, differentiation,

survival, and apoptosis. Proteins that play a role in thispathway are protein G and three protein kinases, namely,MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK),and MAPK. MAPKKK can phosphorylate and activate theMAPK protein kinase (MAPKK), and MAPKK may activateMAPK. hIFNb can inhibit extracellular signal-regulatedkinase (ERK) mitogen ERK kinase (MEK) pathway, whichincludes a group o MAPK pathway. Te pathway responds togrowth actors and differentiation actors. MEK ERK pathwayhas Ras as protein G, Ra as MAPKKK,MEK as MAPKK, andERK as MAPK. Atthe end o the signal transduction pathway,the transcription actor or mRNA genes synthesis that playsa role in the process o cell division is activated [ ].


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IFNAR1 IFNAR2

Tyk-2

STAT

STAT

IRF9

IRF9

ISRE

GAS

Antiproliferative activity

CrkL

JAK-1

STAT-1 STAT-2

STAT-1 STAT-1

STAT-5

IFN-

F : IFN-b signaling via JAK-SA pathway, adapted rom [].

MEK ERK pathway inhibition by hIFNb has beenwidely reported. In experiments, using CD + cells stim-ulated by anti-CD and interleukin- (IL-), it was observedthat hIFNb can prevent the G/G phase o the cell cyclerom entering S phase. As a result, cells cannot perormDNA replication and prolieration does not occur. Severalpublications reported that the inhibition o prolierationoccurred because hIFNb may induce enzymes that caninactivate phosphatases PPA and regulate docking proteinthat inhibits the interaction o ERK with MEK or MEKinteraction with other kinases. Inhibition would decreasethe activity o cyclin-dependent protein kinase (CDK- andCDK-) and decreased the expression o cyclin D and E pro-tein as the driving cell division. Inhibition o p expressionleads to increase p Wa/kip (inhibitor o cell division) anddecrease phosphorylation o RB/p [,].

Mechanism o antiprolieration hIFNb occurs notonly through regulation o protein synthesis and selectivetranslation o proteins involved in inhibition o prolieration,but also through apoptosis as shown in Figure. Tere are

two main pathways o apoptosis in cells that are activated:hIFNb amily receptor signal transduction through tumornecrosis actor alpha (NF-) and the release o cytochromec by mitochondria. Both o these pathways activate cas-pase signaling cascade resulting in DNA ragmentation andcell death. Induction o cell death occurs through NF- receptor amily, namely, NF-a/NF-aR, FasL/Fas, Apo,RAIL/RAILR, and Apo. hIFNb contributes to anincrease in p protein response to stress signaling andactivation o p that plays a role in cell death. Additionally,hIFNb can activate PKR which has a variety o proteinsubstrates such as eukaryotic initiation actor (eIF), NF-KB, IRF-, p, SA, and NF-. Tese proteins may

result in the control o cell division, differentiation, andapoptosis. PKR regulates transcription and translation toproduce proteins Fas, p, and Bax can trigger cell death viacaspase pathway [,,].

Te expression o caspase pathway proteins, such ascaspase- and caspase-, caspase-, caspase-, and caspase-, is also regulated by hIFNb. Caspase pathway is initiatedby DNA damage signaling. Te signal will cut BID proteinand alter mitochondrial membrane permeability to releasecytochrome c. Cytochrome c protein that activates Apa- and caspase- will result in cell death. hIFNb alsoincreases the protein expression o caspase- andcaspase- aswell as caspase- protein that produces DNA ragmentation.Stimulation o insulin receptor subunit (IRS and IRS) acti-

vates phosphatidylinositol-kinase (PIK) as an inducer oapoptosis. Te role o the PIK/mOR pathway in apoptosisremains unclear. PIK has opposite unction. It has beenshown tounctionas a cell survival actoras wellas aninducero apoptosis. In tumor cells, PIK/mOR is necessary onapoptosis afer treatment with IFN-. Te PIK activationalso leads to DNA ragmentation [].

4. The Use of hIFN-2b as Therapeutic Proteinfor Cancer Treatment

Intererons licensed or antitumor applications are hIFN-a(Roeron-A, Hoffmann-La Roche) and hIFN-b (Intron A,Schering-Plough). Te most oncological indication o hIFN-b includes hairy cell leukemia, melanoma, ollicular lym-phoma, renal cell carcinoma, AIDS-related Kaposis sarcoma,and chronic myelogenous leukemia. Te clinical applicationso rhIFN-b can be summarized in able.


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Cyclin DCyclin E/A

DNAfragmentation

Growth factor

Receptor

Src kinase(ShC/Gbr2/SOS)

Raf

Ras

1

ERK Cdc2 CDK

4

pRb E2F

Cyclin E

Cyclin, cdc25

PCNA

9

BimBax

S

G1 M

G2

Cyclin E

Cyclin E

CDK4

CDK2

Cdc2

CDK2

Cyclin A

CDK2

P21

P53

P27

P16P15

Stress/cytokine

UV

MAPKK 3/6

MAPKK 4/7

JNK

P38

Elk1 and

Cell cycle

Stress response

FAD

Caspase-8

Membraneblebbing

BID

Sitokrom c

P53

P2PA

GTPaseRap15

Akt

PI3K

IRS1/2

AntiproliferationApoptosis

MEK1

ERK2

Caspase-7Caspase-3

Caspase-9

Caspase-6

myc and

Apaf-1

MEKK

IFN-2b

TNF

c-jun, Ets1, C-

AFT2

P90 (CREB) and

F : Molecular mechanism o hIFN-b as anticancer: apoptosis induction or cell cycle inhibition. Te big arrow indicatedoverexpression o gene that is regulated by hIFN-b.

.. Hairy CellLeukemia. Hairy cell leukemia is characterized

by mononuclear cells o B-lymphocyte origin in the periph-eral blood that have prominent cytoplasmic projectionsstaining with tartrate-resistant acid phosphatase. It is alsoidentied by its typical pattern o inltration in the bone mar-row and spleen. hIFN-b was rst approved or use in hairycell leukemia in . Te route o administration or hairycell leukemia is subcutaneousand the recommended dose is million U/m2 three times weekly or months []. Te rstreport o successul story o IFN was in . Seven patientsreceived million U o partially puried (leukocyte) humanIFN intramuscularly daily. Tree o seven patients achieved acomplete remission andour a partialremission []. Puried

IFN-b synthesized by using recombinant DNA technol-ogy (Intron A, Schering Corporation) demonstrates similaractivity []. It was also reported that hIFN-b was given

to patients. Te dose was2.0 106 IU/m2 subcutaneouslythree times weekly. At months, there were patientsremaining. During thetwo years o continuous IFNtreatmentnone o the patients showed any signs o relapse. Te IFNtherapy was generally well tolerated, but month evaluationshowed mild toxicity in about % o the patients []. Terewas a study which reported unexpected high incidence osecond neoplasm in patients afer hIFN-b treatments withthe same dose or to months o therapy. Tere were patients rom patients (six were hematopoietic origin

and the remaining were adenocarcinomas) who developed

second neoplasm [].

.. Melanoma. According to the national cancer institute,melanoma is dened as a orm o cancer that begins inmelanocytes. Melanocytes are cells that make the pigmentmelanin. Melanoma may begin in a mole (skin melanoma)but can also begin in other pigmented tissues, such as in theeye or in the intestines. Te use o high dose o IFNb or theadjuvant therapy o stage IIB and III melanoma patients wasapproved by FDA in . A study by Kirkwood et al. [] in patients compared intravenous administration o hIFN-b at MU/m2 or month and subcutaneous administra-tion at MU/m2 or weeks with observation alone. It

was reported that prolongation o disease-ree survival andprolongation o overall survival occurred in comparison toobservation. In , the Scottish melanoma group applieda randomized trial to compare observation alone with months therapy with subcutaneously low dose intereronat MU/day (three times weekly). Te result showed thatthere was a statistically signicant improved disease-reesurvival or up to months []. A Systematic Review oRandomized Controlled rials by Lens and Dawes [] statedthat there wasno clear benet o hIFN-bon overall survivalin melanoma patients. A large randomized controlled trial isneeded to study the effectiveness and beneciary o hIFN-b treatment.


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: Summary o clinical application o rhIFN-b.

No Indication Clinical setting Efficacy Reerences

Hairy cell

leukemia

Seven patients received million U opartially puried (leukocyte) human IFNintramuscularly daily.

Tree o seven patients achieved a complete

remission and our a partial remission. []

hIFN-b was given to patients. Te dosewas . IU/m subcutaneously threetimes weekly.

At months, there were patientsremained. During the two years ocontinuous IFN treatment none o thepatients showed any signs o relapse. TeIFN therapy was generally well tolerated, but month evaluation showed mild toxicity inabout % o the patients.

[]

hIFN-b treatments with . IU/m

dose or to month therapy.

Tere were patients rom patients (sixwere hematopoietic origin and theremaining were adenocarcinomas)developed second neoplasm.

[]

Melanoma

Comparing intravenous administration o

hIFN-b at MU/m

or month andsubcutaneous administration at MU/m

or weeks with observation alone in patients.

Prolongation o disease ree survival andprolongation o overall survival occurred incomparison to observation.

[]

A randomized trial to compare observationalone with months therapy withsubcutaneously low dose intereron at MU/day (three times weekly).

Tere was a statistically signicant improveddisease-ree survival or up to months.

[]

A Systematic Review o RandomizedControlled rials by Lens and Dawes.

No clear benet o hIFN-b on overallsurvival in melanoma patients. A largerandomized controlled trial is needed tostudy the effectiveness and beneciary ohIFN-b treatment.

[]

Follicular

Lymphoma

IFNb has given in the context o relatively

intensive initial chemotherapy at units per month.

Prolongation o survival and remissionduration. []

Rituximab added to rst-line mitoxantrone,chlorambucil, and prednisolonechemotherapy ollowed by intereronmaintenance.

Prolongs survival in patients with advancedollicular lymphoma.

[]

Stage III or stage IV o patients thatreceive either chlorambucil (CB): mgdaily or weeks, ollowed by a -weekinterval, with subsequent -weektreatment periods at the same dose,separated by -week intervals, or, CB givenconcurrently with intereron (IFN). IFN wasgiven at a dose o million units thrice

weekly, subcutaneously, throughout the-week treatment period.

Te role o intereron as initial andmaintenance therapy in patients with newlydiagnosed FL did not demonstrate anyadvantage.

[]

Renal Cell

Carcinoma

Long term o combination hIFN-b andinterleukin- administered subcutaneouslyin patients.

Objective responses was observed in o (%) patients and o whom (%)achieved a complete response. Overallmedian survival is months, six patientswere surviving at a median ollow-up o months, and three (%) are stillprogression-ree.

[]

Nephrectomy ollowed by hIFN-badministration.

Improved survival o metastatic RCCpatients.

[]


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cytogenetic response and patients survival increased whenrhIFN-b was combined with cytarabine [].

5. Conclusions and Future Directions

hIFN-b is a protein that has anticancer activity. It has been

approved by the FDA as a therapeutic protein that can beused to treat some types o cancer, either in monotherapyor combination therapy with other anticancer drugs. Teinormation regarding the side effects o rhIFN-b needsto be well known because its therapeutic use requires a longtime. Development o rhIFN-b to improve the efficacy andsaety o proteins is very important. Te continuous urtherexploration on rhIFN-b will lead to the improvement opatients lie quality.

Conflict of Interests

Te author declares that there is no conict o interests

regarding the publication o this paper.

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