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Introduction

There have been many reviews on physiological active phenols, mainly involving monophenols, catechols, and hydroquinones. However, the resorcinol class (1,3-dihy-droxybenzenes) has received less organized attention. The present review deals with resorcinols, such as resver-atrol (RVT) and flavonoids. The flavonoid class includes genistein, naringenin, flavopiridol, quercetin, and epigal-locatechin. In many cases, other phenolic types are also present. The focus is on cell signaling. The unifying theme includes physiological activity and toxicity. An important feature of these compounds is antioxidant (AO) action. It is interesting that they are also described as pro-oxi-dants. A recent review rationalized the dichotomy (1). In relation to AO action, the phenols behave as donors of electrons or hydrogen atoms. As pro-oxidants, oxidation yields catechols or hydroquinones, which are converted to electron transfer (ET) quinones. Subsequent redox cycling produces reactive oxygen species (ROS), which can result in beneficial effects or in toxicity. The multifac-eted approach provides insight.

This review is the latest in our series involving cell sig-naling in various areas done in a multifaceted manner.

The topics of resorcinols and flavonoids have not been previously examined from this perspective.

Cell signaling, receptors, and physiological activity

Starting more than a decade ago, proposals have been made concerning the fundamental aspect of cell signal-ing. The process is known to be importantly involved in various aspects of biological function, including normal processes, therapeutic drug action, and toxicology. A recent review has provided further insight (2). Evidence has accumulated that ROS, such as hydrogen peroxide, superoxide, and the hydroxyl radical, are important chemical mediators that regulate the transduction of sig-nals by modulating protein activity via redox chemistry. Authors have proposed that ROS have been conserved throughout evolution as universal second messengers. Nearly, every step in signal transfer is sensitive to ROS, which can function as second messengers in the activa-tion of transcription factors.

In effect, cell signaling can be regarded as proceeding via a long redox chain in which the standard parameters of

REVIEW ARTICLE

Cell signaling and receptors with resorcinols and flavonoids: redox, reactive oxygen species, and physiological effects

Peter Kovacic1 and Ratnasamy Somanathan2

1Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, USA and 2Centro de Graduados e Investigación del Instituto Tecnológico de Tijuana, Tijuana, B.C. Mexico

AbstractThere have been appreciable numbers of reviews on monophenols, catechols, and hydroquinones. However, the resorcinol class has received less attention. This review deals with resorcinols and flavonoids. Emphasis is on cell signaling in addition to antioxidant (AO) properties and pro-oxidant effects. The apparent dichotomy is rationalized. There is extensive literature dealing with various aspects of cell signaling in addition to receptor involvement. The physiological responses are provided along with integration into the unifying mechanistic theme of electron transfer (ET)-reactive oxygen species (ROS)-oxidative stress (OS). The multifaceted approach involving redox processes and cell signaling is unique in providing novel insight.Keywords: Resorcinol, flavonoids, stilbenes, cell signaling, bioactivity

Address for Correspondence: Peter Kovacic, Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, USA. Tel: (+619) 594-5595. Fax: (+619) 594-4634. E-mail: pkovacic@sundown.sdsu.edu

(Received 24 February 2011; accepted 04 May 2011)

Journal of Receptors and Signal Transduction, 2011; 31(4): 265–270© 2011 Informa Healthcare USA, Inc.ISSN 1079-9893 print/ISSN 1532-4281 onlineDOI: 10.3109/10799893.2011.586353

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initiation, propagation, and termination pertain, involv-ing omnipresent conduit species with unshared elec-trons. A series of relay stations may be operative. The numerous redox moieties in anchored proteins might fall in the relay category. There has been dramatic increase in attention devoted to free radical species in cell signaling, although the bulk of the signal transduction literature pays no attention to this.

Flavonoids (general)Many studies are accumulating that report the neu-roprotective, cardioprotective, and chemopreventive actions of dietary flavonoids (3). Although a major focus has been on the AO properties, there is an emerging view that flavonoids, and their in vivo metabolites, do not act only as conventional hydrogen-donating AOs, but may also exert modulatory actions in cells through actions at protein kinase and lipid kinase signaling pathways. Inhibitory or stimulatory actions at these pathways are likely to affect cellular function profoundly by altering the phosphorylation state of target molecules and by modulating gene expression. A clear understanding of the mechanisms of action of flavonoids, either as AOs or as modulators of cell signaling, and the influence of their metabolism on these properties are key to the evaluation of these potent biomolecules as anticancer agents, cardioprotectants, and inhibitors of neurode-generation. These views could also apply to other resor-cinols that exhibit AO actions.

Nutritional flavonoids modulate estrogen recep-tor signaling (4). Results indicate that flavonoids act on ERα transcriptional activity, whereas they impair the activation of rapid signaling pathways. The result-ing decoupling of ERα signal transduction could be a new mechanism in the protective effects of flavonoids against cancer. Inhibition of a receptor by red wine flavonoids provides a molecular explanation for the “French paradox” (5). Red wine abrogates the ligand-induced recruitment of signaling molecules and the activation of downstream events. Flavones suppress receptor signaling by down-regulating the expression of the common gamma chain (6). Flavonoids acti-vate receptor-mediated gene expression by inhibiting cyclin-dependent kinases in liver carcinoma cells (7). Skin cancer chemopreventive effects of the flavonoid silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell-cycle progression (8). The effects of flavonones were exam-ined on suppressing the expression of the high-affinity receptor, which plays a central role in the allergic response (9). Studies have demonstrated that certain

flavonoids inhibit platelet function through several mechanisms, including antagonism of a membrane receptor in these cells (10).

ResveratrolResults suggest that multiple signaling pathways may underlie the apoptotic death of glioma induced by RVT (Figure 1) (11). Down-regulation of signaling pathways may be an important mediator in RVT-induced apopto-sis in these cells (12). Resveratrol may exert a protective effect on damage to heart muscle through modulating of the AMPK signaling pathway (13) and modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK activation (14). A study also showed that RVT inhibits PDGF receptor mitogenic signaling in mesangial cells (15). The phenol protects cells from AA + iron-induced ROS production and mitochondrial dysfunction through AMPK-mediated inhibitory phosphorylation of GSK3β downstream of poly(ADP-ribose)polymerase-LKB1 pathway (16). The growth-inhibitory effects of RVT are mediated through cell-cycle arrest, up-regulation, down-regulation, and activation of caspases (17). Resveratrol has been shown to suppress the activation of several transcription fac-tors, to inhibit protein kinases and casein kinase II, and down-regulate products of genes. Resveratrol causes phosphorylation via ATM kinase pathway as a central mechanism for DNA damage (18). The phenol resulted in generation of ROS, subsequent drop in mitochon-drial membrane potential, followed by activation of caspase-3 and caspase-9 and induction of apoptosis (19). In a similar study, RVT was shown to induce acti-vation of caspase-3 and to increase the cleavage of the downstream caspase substrate, poly(ADP-ribose) poly-merase (11). Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor or a selective caspase inhibitor. In a recent study, it was shown that RVT regulates oxidative stress (OS) and mitochondrial AOs in neuronal cells and also activates nuclear factor kappa B (NF-κB) signaling (20). The compound also triggers signaling-dependent

Abbreviations:AO, antioxidant; ET, electron transfer; ROS, reactive oxygen species;

OS, oxidative stress; RVT, resveratrol; EGCG, epigallocatechin gallate

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Figure 1. Resveratrol.

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apoptosis in human tumor cells (21). A similar study showed RVT-induced apoptosis is associated with Fas redistribution and the formation of a death-inducing signaling complex on colon cancer cells (22). In a review, particular attention was given to antagonists and agonists of the Ah-receptor, including various fla-vonoids and RVT (23).

GenisteinGenistein (Figure 2) has been shown to inhibit cell growth and to induce apoptosis in a wide variety of cancer cell lines (24). These cells exhibited a decrease in Akt protein levels and subsequent down-regulation of Akt activity (Akt phosphorylation). Furthermore, genistein treatment induced mitochondrial membrane potential change, caspase-3 activation, and PARP cleavage. Inhibition of Akt signaling pathway and induction of apoptosis by genistein could be used as a new treatment modality for the prevention and/or treatment of malignancies. The phenol inhibits the growth of PC3 prostate cancer cells and induces apoptosis by inhibiting NF-κB and Akt sig-naling pathways (25). Genistein acts by modulating the cellular distribution of actin-binding proteins in associa-tion with alterations of cellular signal transduction path-ways in human stromal cell proliferation (26). A similar study showed inhibition of Akt and NF-κB activity and their cross-talk provide a novel mechanism by which genistein inhibits cell growth and induces apoptotic processes in tumorigenic prostate epithelial cells (27). Genistein may be a natural antidiabetic agent by directly modulating pancreatic β-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway (28). An article reviews studies regarding the effects of natural chemopreventive agents, such as isoflavones and EGCG, on cancer-related cell signaling pathways and provides comprehensive knowledge of the biologi-cal and molecular roles of chemopreventive agents in cancer cells (29). Results suggest that cell signaling and regulators of cell cycle are potential epigenetic molecular targets for prostate cancer prevention by dietary agents, for example, genistein and EGCG, against human pros-tate cancer (30).

NaringeninNaringenin (Figure 3) inhibits allergen-induced airway inflammation and inhibits NF-κB activity in a murine model of asthma (31). Data demonstrate that naringenin can exert antifibrogenic effects by directly or indirectly

down-regulating protein expression and phosphoryla-tion through transforming growth factor-1 signaling (32). Data suggest that naringenin inhibits β-catenin/Tcf signaling in gastric cancer with unknown mechanisms (33). Naringenin inhibits apolipoprotein B secretion through activation of both P13-K and MAPK signaling (34). The phenol suppresses cell growth and migration via alternative signaling pathways (35). Results indicate a potential modulation of bacterial cell–cell communi-cation by flavonoids, especially naringenin, quercetin, sinestin, and apigenin (36). Among the tested flavonoids, naringenin emerged as potent and possibly a nonspecific inhibitor of autoinducer-mediated cell–cell signaling. Mechanisms of naringenin-induced apoptotic cascade in cancer cells and involvement of estrogen receptor α and β signaling were reported (37). Naringenin improves insulin signaling and sensitivity and thereby promotes the cellular actions of insulin (38). The compound sig-nificantly reduces lung metastases in mice with pulmo-nary fibrosis and increases their survival by improving the immunosuppressive environment through down-regulating transforming growth factor-β1 and reducing regulatory T cells (39). Naringenin derivatives differently regulate apoptosis of cells via intracellular ROS produc-tion coupled with the concomitant activation of the caspase cascade signaling pathway, thereby implying that hydroxylation may be critical for the apoptosis-inducing activity of flavonoids (40). Results suggest that naringenin may produce an anti-inflammatory effect in stimulated glial cells that may be due to its interaction with p38 signaling cascades and the STAT-1 transcription factor (41). Hesperetin and naringenin prevent tumor necrosis factor alpha (TNF-α) from down-regulating the transcription of two anti-lipolytic genes. These effects are mediated through the inhibition of the ERK pathway (42). Naringenin impaired estrogen receptor (ER) α sig-naling by interfering with ER-mediated activation of ERK and phosphoinositide 3-kinase signaling pathways (43). Co-exposure to naringenin, the ligand for ER, specifically antagonizes rapid signals by reducing the effect of the endogenous hormone in promoting cellular prolifera-tion (44).

QuercetinQuercetin (Figure 4) decreases the survival of prostate cancer cells by modulating the expression of insulin-like

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Figure 2. Genistein.

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Figure 3. Naringenin.

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growth factors system components, signaling molecules and induces apoptosis (45). Quercetin induces apoptosis via AMPK activation and p53-dependent apoptotic cell death and it may be a chemopreventive or therapeutic agent against colon cancer (46). Quercetin may induce neuronal death via a mechanism involving inhibition of neuronal survival signaling through the inhibition of both Akt/PKB and ERK (47). Inhibition of epidermal growth factor receptor kinase is an integral part of quercetin-induced growth inhibition in colorectal cells (48).

FlavopiridolFlavopiridol (Figure 5) inhibits phosphokinases (49). Its activity is strongest on cyclin-dependent kinases and less on receptor tyrosine kinases, receptor associates tyrosine kinases and on signal-transducing kinases. The cytotoxic activity of flavopiridol is not limited to cycling calls. Resting cells are also killed. Results show for the first time that flavopiridol modulates specific cellular signal transduc-tion pathways in B-CLL cells, thereby altering the balance between survival and cell death signals and providing rationale for the p53 independent nature of flavopiridol-induced apoptosis (50). Further work is required to identify whether combinations of conventional chemotherapeutic drugs and novel agents like flavopiridol can be used to improve patient outcomes in the treatment of B-CLL. Flavopiridol has pleiotropic effects on key targets involved with survival of dormant breast cancer cells and may rep-resent a useful approach to eliminating cells dependent on multiple signal pathways for survival (51). Results clearly suggest that the phenol interferes with TNF cell signaling pathway, leading to suppression of anti-apoptotic mecha-nism and enhancement of apoptosis in tumor cells (52). Flavopiridol and trastuzumab synergistically inhibit prolif-eration of breast cancer cells (53). There is association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways.

Epigallocatechin gallateEpigallocatechin gallate (EGCG) (Figure 6) induces apoptosis by activating caspase-3/caspase-7 and inhibit-ing the expression of Bcl-2 and survinin, suggesting the blockade of signaling involved in early metastasis (54). Quercetin synergizes with EGCG in inhibiting the self-

renewal properties of cancer stem cells CSCs, inducing apoptosis, and blocking CSCs migration and invasion. Catechin, a constituent of tea, possesses bioactivities. In particular, the most abundant catechin in tea is EGCG, which has an anti-inflammatory effect (55). Production of interleukin-6 and RANKL was suppressed in the osteo-blasts treated with EGCG, which indicated an inflamma-tion suppression effect in osteomyelitis treatment. EGCG has been shown to modulate multiple signal transduction pathways in a fashion that controls the unwanted prolif-eration of cells, thereby imparting strong cancer chemo-preventive as well as therapeutic effects (56). A review discusses the modulations of important signaling events by the phenol and their implications in cancer manage-ment. Cell signaling pathways in the neuroprotective actions of EGCG were examined, with implications for neurodegenerative diseases (57). EGCG regulates T-cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase (58). EGCG acts to selectively inhibit epi-dermal growth factor-dependent kinases to inhibit cell proliferation (59). Studies reveal the possible benefits of green tea polyphenols as cancer therapeutic agents to inhibit Met signaling and potentially block invasive cancer growth (60). A report deals with suppression of

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Figure 4. Quercertin.

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Figure 5. Flavopiridol.

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Figure 6. Epigallocatechin.

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androgen receptor signaling and prostate-specific anti-gen expression by EGCG in different progression stages of prostate cancer cells (61). The phenol inhibits cell signal-ing by inducing gene expression (62). A report deals with the effects of EGCG on epidermal growth factor receptor signaling pathways, gene expression, and chemosensitiv-ity in human carcinoma cells (63).

Acknowledgement

Editorial assistance by Thelma Chavez is acknowledged.

Declaration of interest

The authors declare no conflict of interest.

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