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Review Piper Betel Leaf: A Reservoir of Potential Xenohormetic Nutraceuticals with Cancer-Fighting Properties Sushma R. Gundala and Ritu Aneja Abstract Plants contain a much greater diversity of bioactive compounds than any man-made chemical library. Heart-shaped Piper betel leaves are magnificent reservoirs of phenolic compounds with antiproliferative, antimutagenic, antibacterial, and antioxidant properties. Widely consumed in South Asian countries, the glossy leaf contains a multitude of biophenolics such as hydroxychavicol, eugenol, chavibetol, and piperols. Convincing data underscore the remarkable chemotherapeutic and chemopreventive potential of betel leaves against a variety of cancer types. The leaf constituents modulate an extensive array of signaling molecules such as transcription factors as well as reactive oxygen species (ROS) to control multiple nodes of various cellular proliferation and death pathways. Herein, we provide an overall perspective on the cancer- fighting benefits of the phenolic phytochemicals in betel leaves and a comprehensive overview of the mechanisms responsive to dose-driven ROS-mediated signaling cascades conscripted by bioactive phenolics to confer chemotherapeutic and chemopreventive advantages. Intriguingly, these ROS-triggered responses are contextual and may either elicit a protective xenohormetic antioxidant response to premalignant cells to constitute a chemopreventive effect or generate a curative chemotherapeutic response by pro-oxidatively augmenting the constitutively elevated ROS levels in cancer cells to tip the balance in favor of selective apoptosis induction in cancer cells while sparing normal ones. In conclusion, this review provides an update on how distinct ROS levels exist in normal versus cancer cells and how these levels can be strategically modulated and exploited for therapeutic gains. We emphasize the yet untapped potential of the evergreen vine, betel leaf, for chemopreventive and chemotherapeutic management of cancer. Cancer Prev Res; 7(5); 477–86. Ó2014 AACR. Introduction Mankind has relied on plants as a source of medicine for eons. Unsurprisingly, plants contain a much greater diver- sity of bioactive compounds than any known man-made chemical library. Even today, as much as 80% of the population in developing countries banks on medicinal plants as their only affordable source of medication (1). No wonder nature has been a matchless source of multicom- ponent concoctions and single compounds ranging from simple phenolics to complex alkaloids that have been developed over the millennia to modulate various cellular mechanisms for therapeutic gains. The myriad benefits of these natural products, which actually emerged because of the interactions among plants and their surrounding envi- ronment to enhance survival, are prodigious and well appreciated in every aspect of life. Furthermore, the wide variety of compounds like vitamins, carotenoids, flavo- noids, isothiocyantes, sulfides, thiols, phenols, and alka- loids in plant extracts have helped cure and/or manage several chronic conditions like diabetes, hepatitis, arthritis, cardiovascular, cerebrovascular diseases, and cancer. Can- cer, a malicious disease that gripped mankind since its dawn in early in fourth century BC (2), has been an alarmingly increasing cause of death worldwide over the past 20 years. Continuing research efforts to identify a cure for cancer have met with limited success, and the war against this deadly neoplasm is growing stronger by the day. Most pharmaceu- tical compositions of various purified compounds and crude chemopreventive and chemotherapeutic formula- tions today are from the inexhaustible chemical inventory of plants. Current chemotherapy: one size does not fit all The greatest impact of plant-derived drugs has been in the anticancer area, wherein the development of plant-derived drugs such as taxol, vinblastine, vincristine, and camptothe- cin has proven to be a boon in the treatment of some of the deadliest cancers. This perhaps fueled the notion that single constituents of medicinal plants dictate their pharmacolog- ic activity. Although this paradigm has resulted in several outstanding synthetic drug molecules and many more entering the pipeline of clinical trials, it is rather dismaying that about 60% of drug candidates either fail late-stage Authors' Afliation: Department of Biology, Georgia State University, Atlanta, Georgia Corresponding Author: Ritu Aneja, Department of Biology, Georgia State University, Atlanta, GA 30303. Phone: 404-413-5417; Fax: 404-413-5300; E-mail: [email protected] doi: 10.1158/1940-6207.CAPR-13-0355 Ó2014 American Association for Cancer Research. Cancer Prevention Research www.aacrjournals.org 477 Research. on April 13, 2016. © 2014 American Association for Cancer cancerpreventionresearch.aacrjournals.org Downloaded from Published OnlineFirst January 21, 2014; DOI: 10.1158/1940-6207.CAPR-13-0355

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Page 1: Piper Betel Leaf: A Reservoir of Potential Xenohormetic ...insanemedicine.com/wp-content/...Leaf...Nutraceuticals-with-Cancer-Fighting-Properties.pdfcombination of betel leaf with

Review

Piper Betel Leaf: A Reservoir of Potential XenohormeticNutraceuticals with Cancer-Fighting Properties

Sushma R. Gundala and Ritu Aneja

AbstractPlants contain a much greater diversity of bioactive compounds than any man-made chemical library.

Heart-shaped Piper betel leaves are magnificent reservoirs of phenolic compounds with antiproliferative,

antimutagenic, antibacterial, and antioxidant properties. Widely consumed in South Asian countries, the

glossy leaf contains amultitude of biophenolics such as hydroxychavicol, eugenol, chavibetol, and piperols.

Convincing data underscore the remarkable chemotherapeutic and chemopreventive potential of betel

leaves against a variety of cancer types. The leaf constituents modulate an extensive array of signaling

molecules such as transcription factors as well as reactive oxygen species (ROS) to control multiple nodes of

various cellular proliferation and death pathways. Herein, we provide an overall perspective on the cancer-

fighting benefits of the phenolic phytochemicals in betel leaves and a comprehensive overview of the

mechanisms responsive todose-drivenROS-mediated signaling cascades conscriptedbybioactive phenolics

to confer chemotherapeutic and chemopreventive advantages. Intriguingly, these ROS-triggered responses

are contextual andmay either elicit a protective xenohormetic antioxidant response to premalignant cells to

constitute a chemopreventive effect or generate a curative chemotherapeutic response by pro-oxidatively

augmenting the constitutively elevated ROS levels in cancer cells to tip the balance in favor of selective

apoptosis induction in cancer cells while sparingnormal ones. In conclusion, this reviewprovides anupdate

on how distinct ROS levels exist in normal versus cancer cells and how these levels can be strategically

modulated and exploited for therapeutic gains. We emphasize the yet untapped potential of the evergreen

vine, betel leaf, for chemopreventive and chemotherapeutic management of cancer. Cancer Prev Res; 7(5);

477–86. �2014 AACR.

IntroductionMankind has relied on plants as a source of medicine for

eons. Unsurprisingly, plants contain a much greater diver-sity of bioactive compounds than any known man-madechemical library. Even today, as much as 80% of thepopulation in developing countries banks on medicinalplants as their only affordable source of medication (1). Nowonder nature has been a matchless source of multicom-ponent concoctions and single compounds ranging fromsimple phenolics to complex alkaloids that have beendeveloped over the millennia to modulate various cellularmechanisms for therapeutic gains. The myriad benefits ofthese natural products, which actually emerged because ofthe interactions among plants and their surrounding envi-ronment to enhance survival, are prodigious and wellappreciated in every aspect of life. Furthermore, the widevariety of compounds like vitamins, carotenoids, flavo-

noids, isothiocyantes, sulfides, thiols, phenols, and alka-loids in plant extracts have helped cure and/or manageseveral chronic conditions like diabetes, hepatitis, arthritis,cardiovascular, cerebrovascular diseases, and cancer. Can-cer, amalicious disease that grippedmankind since its dawnin early in fourth century BC (2), has been an alarminglyincreasing cause of death worldwide over the past 20 years.Continuing research efforts to identify a cure for cancer havemet with limited success, and the war against this deadlyneoplasm is growing stronger by the day. Most pharmaceu-tical compositions of various purified compounds andcrude chemopreventive and chemotherapeutic formula-tions today are from the inexhaustible chemical inventoryof plants.

Current chemotherapy: one size does not fit allThe greatest impact of plant-derived drugs has been in the

anticancer area, wherein the development of plant-deriveddrugs such as taxol, vinblastine, vincristine, and camptothe-cin has proven to be a boon in the treatment of some of thedeadliest cancers. This perhaps fueled the notion that singleconstituents of medicinal plants dictate their pharmacolog-ic activity. Although this paradigm has resulted in severaloutstanding synthetic drug molecules and many moreentering the pipeline of clinical trials, it is rather dismayingthat about 60% of drug candidates either fail late-stage

Authors' Affiliation: Department of Biology, Georgia State University,Atlanta, Georgia

Corresponding Author: Ritu Aneja, Department of Biology, Georgia StateUniversity, Atlanta, GA 30303. Phone: 404-413-5417; Fax: 404-413-5300;E-mail: [email protected]

doi: 10.1158/1940-6207.CAPR-13-0355

�2014 American Association for Cancer Research.

CancerPreventionResearch

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clinical development or shortly after entering the marketdue to debilitating toxicity, limited efficacy, or emergence ofdrug resistance (3). One obvious explanation for thesefailures is that disease pathogenesis involves dysregulationof multiple molecular pathways and thus the "silver bullet"approach ofmonotargeting yields limited efficacy. Paradox-ically, the multifactorial nature of cancer requires a pleio-tropic approach wherein a whole plant extract, a multicom-ponent concoction, or a fractionated mixture of phyto-chemicals or even a single agent can simultaneously hitmultiple targets in consecutive or parallel pathways toachieve optimal clinical efficacy.

Plant extracts: phytochemical potions withmiraculousmedicinal powers

Owing to the unmistakable promise of herbal medica-tions, there is an ever-increasing quest for new plants thatcould possibly hold the key to prevent or eliminate thisdreaded disease by conferring superior chemopreventive orchemotherapeutic properties. The secondary metabolitesproduced by plants, referred to, as phytochemicals are oftenplant stress signalingmolecules, which have been identifiedto resist stress, fight disease, and improve longevity inanimals consuming them, a phenomenon known as xeno-hormesis (4–7). Indeed the phytochemicals present in fruitsand vegetables (e.g., carotenoids, polyphenolics, anthocya-nins, terpenes, alkaloids) are functionally pleiotropic; theypossess multiple intracellular targets, affecting different cellsignaling cascades usually altered in cancer cells with lim-ited toxicity to normal cells. However, the host of disease-combating chemicals is not limited to fruits and vegetables,but is widely spread across the major ingredients of ourcuisines, spices, and herbs. The nutraceuticals derived fromspices and herbs have also been shown to modulate mul-tiple targets, including the transcription factors (NF-kB,Nrf2, hypoxia-inducible factor-1a), kinases, and inflamma-tion markers (8). However, there still exist several unex-plored exotic condiments with promising disease-fightingpotential.

Some plants have it all: the versatile pharmacopoeia ofPiper betel leaves

Although known from ancient times, scientific interest inPiper betel, an evergreen vine, was restricted owing to mis-conceptions largely due to the consumption of betel quid, acombination of betel leaf with areca nut, slaked lime, andtobacco, which is a storehouse of several carcinogens andhas been linked to the development of oral cancer (9–11).Recent years have seen a rekindled interest in pursuing thismember of the natural medicine chest, and several labora-tories, including ours, have begun to examine themedicinalpowers of this magnificent plant using a rationale-drivenscientific approach. A perennial creeper of the Magnolio-phyta family, the Piper betel plant with glossy and heart-shaped leaves flourishes in warm and humid environmentsand can grow up to one meter in length (12). Although theplant originally hails from India, over the past severaldecades, it has gained popularity amongst other South

Asian countries such as Sri Lanka, Indonesia, Nepal, Paki-stan, Malaysia, Thailand, and Singapore (12). No wonderthese leaves are recognized as "Green Gold" due to theirhigh demand in the South Asian countries (13). These betelleaves are widely cultivated in most parts of South andSoutheast Asia, including India, Bangladesh, Pakistan, SriLanka, Nepal, Burma, Vietnam, Papua New Guinea, Thai-land, Taiwan, and Malaysia. The cultivation of these leavesismostly limited to areaswithmoderate climatic conditionsaccompanied by high humidity. The harvested leaves arealso exported to other parts of Asia, Middle East, Europe,and the United States.

Given that it is a cheap and readily accessible naturalproduct, various parts of the Piper betel plant especially betelleaves, are used in traditional medicine for treatment ofseveral conditions such as abscesses, constipation, conjunc-tivitis, itches, rheumatism, abrasions, and many more (14,15). Although the roots of Piper betel have served as alter-native oral contraceptives, the oil obtained frombetel leaveshas bactericidal action (13). Consumption of betel leaveshas also been known to stimulate feelings of well-being,amplified salivation, perspiration, alertness and a sense ofincreased energy, and warmth (13). A meticulous evalua-tion of the leaf as a whole and its constituents has yieldedmany more medicinal properties such as antifungal, anti-microbial, wound healing, antioxidant, antimutagenic, andchemopreventive activities (refs. 12, 16; Fig. 1).

Here below, we attempt to synopsize existing knowledgeon the cancer-fighting properties of betel leaf and its phy-tochemical constituents, and present an overview of cellularnuances driven by phenolic phytochemicals that triggerreactive oxygen species (ROS)-mediated signaling circuit-ries to launch a two-pronged offensive; one that underlieschemopreventative benefits produced by a potential xeno-hormetic response which fortifies the antioxidant defensesystem in premalignant cells, and the other that undergirdschemotherapeutic efficacy due to the induction of apoptosisby overwhelming the cellular ROS content.

Betel leaves: abundant repositories of cancer-fightingphytochemicals

An enriched source of calcium, vitamin C, niacin, thia-mine, carotene, and riboflavin (17), betel leaves are clearlyassociated with nutritive benefits. Thus, referring to them asbetel nutraceuticals is supported and well reasoned. Otherbetel phytochemicals include allylpyrocatechol (APC; 2-hydroxychavicol), 4-hydroxycatechol, b-caryophyllene,methyl eugenol, carotenes, starch, diastases, and an essen-tial oil containing hydroxychavicol (18, 19). Hydroxycha-vicol, a phenolic compound quantitatively present atapproximately 26% in betel leaves, has been shown to exertantiproliferative activity in prostate cancer (20). Hydroxy-chavicol has also been shown to impede cell-cycle progres-sion of prostate cancer andoral KB carcinoma cells (20–22).Several reports indicate hydroxychavicol as an antimuta-genic agent (12, 23) as well as an effective inhibitor ofcyclooxygenase (COX), platelet calcium signaling, andthromboxane B2 production (21). Other studies suggest

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that hydroxychavicol also known as APC possesses anti-ulcerogenic activity (24) and has been shown to alleviateindomethacin-induced stomach ulceration leading to gas-tric cancer (25). Hydroxychavicol also inhibits inflamma-tory responsemolecules like inducible nitric oxide synthaseand COX-2, which are known to enhance tumor growth bydownregulation of the NF-kB) pathway (24). Chavibetol(CHV), along with hydroxychavicol, acts as a radioprotec-tant (25), and exhibits substantial immunomodulatory andfree radical scavenging activities (25). We have shown thatCHV synergizes with hydroxychavicol to exert antiprolifera-tive activity against human prostate cancer PC-3 cells (20).Betel leaf contains large amounts of safrole, which is rapidlydegraded in the human body into dihydroxychavicol andeugenol, the antimutagenic agents, which are then excreted

via the urine (26, 27). Chlorogenic acid (ChA), anotheractive ingredient isolated from betel leaves, has beenreported to eliminate cancerous cells without harmingnormal cells, unlike most conventional chemotherapeutics(13). In addition to cytotoxic and antimutagenic properties,the betel bioactive constituents have been studied for theiroxidative properties (ref. 28; Fig. 1). For example, highhydroxychavicol concentrations provoke its pro-oxidantbehavior as demonstratedby inductionof oxidative damagein liver cancer cells (29). Interestingly, hydroxychavicol wasfound to be a potent antioxidant at lower doses in oral KBcarcinoma, whereas high doses led to apoptosis inductionby increasing ROS levels (22).

Thus, similar to other plant-derived phenolic phyto-chemicals, bioactive betel constituents as single agents exert

Figure 1. Betel leaf nutraceuticals target multiple cellular events and play a crucial role in inhibiting tumor growth, inflammation by decreasing the levels ofcyclooxygenases, COX-1 and COX-2 (21) and stress-inducing events like lipid peroxidation. Furthermore, they activate detoxifying enzymes andupregulate the expression of ABCA1 (ATP-binding cassette transporter) and Liver X receptors, while inhibiting LDL oxidation (62), increase free radicalscavenging, and induce apoptosis signified by increased levels of cleaved caspase-3 and PARP levels (20, 63). The betel leaf constituents killcancer cells by inducing oxidative DNA damage demonstrating their pro-oxidant role (29). PARP, poly (ADP-ribose) polymerase.

Piper Betel Leaf: Anticancer Benefits

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paradoxical anti- and pro-oxidant activities contextually.Given that plant extracts are invariably multicomponent,their activities can perhaps be more representative of anaveraged "profile" of anti- and pro-oxidant behavior, whichmay be an additive summation or an even more complexsynergistic interaction among the individual components.There are a lot of conflicting reports on ROS-quenchingantioxidant mechanisms and ROS-generating pro-oxidantones that are believed tomajorly drive the chemopreventiveand chemotherapeutic agenda in preneoplastic and neo-plastic cells, respectively. This calls into question the unam-biguity in defining a framework for an accurate assessmentof the chemopreventive and/or chemotherapeutic contri-butions of these two-faced phytochemicals. Here below, werevisit the paradoxical roles of plant phytochemicals ingeneral to better comprehend the versatility of the phenolicfunctionality in betel phytochemicals as a double-edgedsword.

Chemotherapeutic (toxic pro-oxidant) andchemopreventive (protective antioxidant) activitiesof plant phytochemicals: two healthful sides of thesame coin

Themost well studied health-promoting phytochemicals(epigallocatechin gallate, curcumin, resveratrol, quercetin,caffeic acid, rutin, gingerols, ChA, etc.) belong to the phenolsuperfamily. In particular, for betel leaves, the versatilephenolic compounds include hydroxychavicol, eugenol,CHV, piperol, and ChA, and can also serve as examples ofsecondary metabolites. These compounds merit a specialmention, as they are the primary defense molecules ofplants and have protected them during evolution. In addi-tion, these phenolics have "chemically" contributed tomaintain an ecological equilibrium between plants andother living organisms feeding on them, including us,humans. The magnanimous nature of these betel leaf com-pounds can be attributed to the inherent physicochemicalproperties packaged within the phenol functional group.

The phenol groups in plants offer remarkable molecularflexibility resulting in an apparent dichotomy associatedwith the versatile phenolic function.Most betel constituentsare composed of an amphiphilic moiety with the hydro-phobic nature of its planar aromatic nucleus coupled withthe hydrophilic character of its polar hydroxyl group, whichcan act as a hydrogen-bond donor or as an acceptor. Thepresence of flavonoids, polyphenols, terpenoids, and alka-loids (30) in betel leaves makes them a remarkable sink aswell as a source for ROS thus conferring antioxidant as wellas pro-oxidant traits to the leaf extract. As alluded to earlier,the paradoxical traits (antioxidant and pro-oxidant) of betelnutraceuticals empower them to offer both chemothera-peutic (cancer cells) and chemopreventive benefits (prema-lignant cells), albeit through different mechanisms (8, 31–34). Once preneoplastic cells undergo malignant transfor-mation into cancer cells, they can perhaps only be elimi-nated through chemotherapeutic strategies, as uponbecom-ing cancerous, these cells have surpassed their amenabilityto chemopreventive measures.

Unlike normal cells, cancer cells owing to their enhancedmetabolic activity have constitutively higher levels of ROS,which spawn a persistent pro-oxidative environment (35–37). Nonetheless, cancer cells despite high ROS concentra-tions, survive by adapting to the increased oxidative stressby upregulating prosurvival mechanisms and altering theirantioxidant systems (Fig. 2).

Normal cells, however, operate within an "optimal win-dow" to maintain a redox balance between generation andeliminationof free radicals, but alsopossess a robust capacityto tolerate a sizeable fluctuation in ROS levels. In contrast,cancer cells with already high basal ROS levels have a much"narrower" window to endure elevations in ROS levels.This "vulnerability" or susceptibility of cancer cells can beexploited by whole betel extract (or its constituent phyto-chemicals) to selectively kill cancer cells by augmenting ROSlevels beyond the toxic threshold that cancer cells can with-stand (Fig. 3). Nevertheless, a "similar-scaled" pro-oxidant

Figure 2. This figure representsthe fate of cancer cells undervarying ROS levels. Cancer cellshaving moderate levels of ROStend to adapt to the stressconditions and show enhancedexpression of prosurvivalmolecules. When betelnutraceuticals interfere with thissituation, causing the moderateROS levels to increaseover the threshold, the cancercells can no longer withstand theoxidative stress and thus arekilled via various possiblemechanisms (12, 22, 27, 29, 37,38, 45, 47, 62, 64–66).

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deviation from redox homeostasis is well tolerated by nor-mal cells. This partly explainswhyplant-based foods, includ-ing betel extract with a concoction of free radical scavengingand generating agents, are well tolerated and nontoxic. Thewidth of the "therapeutic window" may be evaluated by theredox differences between normal and tumor cells and maybe specific to the nature of the components present in theplant-based food.Several reports highlight the pro-oxidant capabilities of

major betel leaf constituents like hydroxychavicol andeugenol. Hydroxychavicol has been shown to exploit thishigher ROS level in cancer cells, and increases it even furtherto preferentially kill them while having no effect on theproliferation of normal cells (22, 38). However, thesephenolic compounds exhibit anti- and/or pro-oxidantbehavior depending on their relative concentrations in vivoalong with the redox potential of the surrounding areas.Interestingly, phenolics can promote oxidation at elevatedconcentrations of the quinone form, where they can act asreducing agents causing an increase in ROS species in theform of a phenoxyl radical, which could be detrimental.This pro-oxidant behavior of phenolic compounds dependson (i) the total number of hydroxyl groups, which result inincreased production of hydroxyl radicals and in somecases, promote production of hydrogen peroxide, (ii) pres-ence of free transition metal ions like Cu (II), involved in

oxidation processes initiating free radical formation, and(iii) co-oxidation of phenoxyl radicals with NADH, causingimproved oxygen uptake and superoxide formation due tothe action of peroxidases (39–43). Moreover, the redox-inactive metals like zinc and calcium have also beenreported to increase the pro-oxidative nature of certainphenolics (44, 45). In addition, due to the initiation offree-radical chain reactions in the cell membranes, thesephenoxyl radicals are stabilized to stay within the cell for alonger time, thus mounting a cytotoxic effect (46). Amongeugenol and isoeugenol, the phenylpropene isomers foundinbetel leaves, the latter has been shown to inducehighROSlevels thus proving to be cytotoxic, whereas eugenol has alsobeen implicated in ROS-independent cytotoxic mechan-isms (47).

Betel nutraceuticals offer chemopreventive benefits:potential "xenohormetics"

A rekindled scientific interest in betel leaves has spurredseveral studies focusedon investigating the chemopreventiveproperties of betel leaves. More evidence to support thepotential benefitsof betel leaves came fromthe identificationof antimutagenic properties of betel leaf constituents, espe-cially hydroxychavicol, which repressed oral carcinogenesisinduced by standard mutagens like benzo[a]pyrene anddimethylbenz[a]anthracene in hamsters (48), and tobac-co-specific nitrosamines like 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK) and N0-nitrosonornicotine(NNN) inmice (49, 50),whenbetel leaf extractwas topicallyapplied. In addition, b-carotene and a-tocopherol of betelleaf extract caused prolonged latency, regression of estab-lished tumors, and decrease in tumor incidence and tumorsize in Syrian hamsters exposed to another mutagen namedacetoxymethyl nitrosamine, thus indicating a strong chemo-preventive effect of betel leaves (51).

Furthermore, studies involving effects of betel leavesagainst 7,12-dimethylbenz(a)anthracene (DMBA)-inducedbreast cancer provided remarkable cues emphasizing theirchemopreventive efficacy. It was observed that when betelleaf extract was fed to rats bearing mammary tumors in theinitiationphase, the tumor growthwasprevented,while ratswith fully developed mammary tumors failed to show anyreduction/inhibition in tumor growth (52, 53). We haverecently reported that betel leaf extract exhibits significantefficacy in inhibiting growth of prostate cancer xenografts(20). These studies generate compelling foregrounds towarrant future investigation of chemopreventive efficacy ofbetel leaves and/or bioactive betel leaf constituents inappropriate animal models.

Insights into the mechanistic actions of betel leaf consti-tuentswereobtained fromseveral investigations that focusedon the effect of betel leaf on gastric carcinomas. For instance,eugenol, hydroxychavicol, b-carotene, and a-tocopherolwere identified to be key players in suppressing ben-zo[a]pyrene-induced neoplasms of the gut in mice, whenbetel leaf extract was mixed with drinking water (49). Euge-nol was further proven to be inducing intrinsic apoptosis inWistar rats bearing N-methyl-N-nitro-N-nitrosoguanidine–

Figure 3. "Achilles heel" of cancer cells. The illustration depicts thelevels of ROS in normal, initiated, and cancer cells. The ROS levelsin normal cells are "basal," while they are slightly elevated in an "initiated"premalignant cell. When these levels elevate beyond a threshold,cell proliferation and survival are promoted (as observed in case ofcancer cells). The ROS levels in cancer cells are in the "caution" zone,which, due to exogenous agents like betel nutraceuticals exertingpro-oxidant behavior by possible depletion of cellular glutathione (GSH)levels (22),might increaseabove theROS thresholdpushing them into the"danger" zone, thus inducing apoptosis. This unique feature, whichmakes the cancer cells vulnerable to death, can be exploited toselectively kill them, while not harming the surrounding normal cells.

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induced gastric cancer by modulating Bcl-2 family proteinsalong with Apaf-1, cytochrome C, and caspases (54). Fur-thermore, studies involving specific carcinogens likeDMBA),which are well known to cause skin cancer, revealed thesignificance of b-cartotene and a-tocopherol in inhibitingthe onset of tumors in mice. Simultaneously, althoughhydroxychavicol exhibited the same response, but to agreater extent, eugenol, however, could only offer limitedprotection against DMBA-induced skin tumors (55). Otherstudies by Azuine and colleagues suggested that eugenol inthe betel leaves exhibited specific antiproliferative activitywhile partially triggering apoptosis (56) along with elicitingsuperoxide formation, lipid peroxidation, and radical scav-enging activity, thus illustrating its antioxidant effects (57).Eugenol was also shown to hinder the upstream signalingmolecule NF-kB, a key player in regulating the expression ofgenes controlling cell proliferation and survival (57).

Despite the existence of strong evidence to demonstratethat betel phytochemicals exert a diverse spectrum of ben-eficial protective and curative effects in various diseasemodels, there are several perplexing questions that awaitpersuasive answers—How can the same polyphenolic phy-tochemical (such as hydroxychavicol from betel leaf) "pre-vent" cancer by exercising chemopreventive strategies aswell as offer "treatment" by enforcing curative commandsfor therapeutic gains? How can the long-accepted antioxi-dant-free radical quenching/scavenging properties of phe-nols explain their chemopreventive and/or chemothera-peutic benefits of betel leaves?How canwe correlate efficacyof these phenols with their antioxidant capacity?

We have alluded to in the above section how polyphe-nolic compounds in whole betel extract with their biophy-sicochemical "flexibility" can tip the redox balance in favorof death in cancer cells by taking advantage of their inher-ently higher ROS levels, which turns out to be their "Achillesheel." Nevertheless, it is difficult to reconcile several of thesequestions in the chemopreventive context in the absence ofa unifying new paradigm called "xenohormesis," which isgaining momentum. This hypothesis assumes that poly-phenols were synthesized by common ancestors of plantsand animals (58). Despite the evolutionary divergence ofthe respective kingdoms, it is intriguing that many crucialmammalian enzymes and receptors have been conservedwhich can be regulated and modulated by plant-producedphytochemicals.

Paramount interest centers on the belief that adverseenvironmental conditions or stress induce the synthesis ofphytochemicals, including polyphenols, in plants. Interest-ingly, when ingested by humans, these phytochemicals upre-gulate the pathways that provide stress resistance in animals(Fig.4).Conceivably, this suggests thathumans that consumephytochemicals via plant-based foods have sensing mechan-isms (enzymes/receptors) toperceive these chemical cues andelicit beneficial responses that enhance the well-being ofhumans thus imparting overall health benefits. This phe-nomenon has been brilliantly termed as "xenohormesis"byHowitz and Sinclair fairly recently in 2008, wherein xenos,is the Greek word for stranger, and hormesis, the term forhealth benefits (58). In simplistic terms, it is health benefitsconferred by a stranger! We envision that ingestion of

Figure 4. Xenohormetic response.The bioactive phenolics of betelleaves may facilitate eliminationof initiated cells, thus ensuringthat they do not develop intocancer. By "signaling" that thereis some "stress" in theenvironment, ingested betelnutraceuticals are thought topotentiate a systemic stress-combating response in normalcells, which in turn triggers theupregulation of endogenousantioxidant enzymes bymodulating the nucleartranscription factor erythroid 2p45(NF-E2)–related factor 2 (Nrf2)expression or the endogenous thiolglutathione (GSH) levels (7, 67).Because of the systemic activationof this defense system,the initiated cells can be effectivelyscavenged and eliminated,presumably by the immunesystem, which is placed on "high-alert." On the other hand, in thecancer cells an opposite effectof further stress induction isobserved because of whichapoptosis is induced (20) and/orthe endogenous Nrf2 and thiollevels are depleted (7, 67).

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phytochemicals causes the body to be tricked into believingthat it is under some kind of stress, which triggers a system-wide response to combat stress.While normally, the presenceof a handful of initiated or premalignant cells would not beable to trigger a sufficiently strong signal for the body toperceive and respond to, phytochemicals may place thesystem on "high-alert" and stimulate a heightened stressresponse that could effectively eliminate initiated or prema-lignant cells thus emphasizing the workings of plant phyto-chemicals in the chemopreventive context (Fig. 4).The polyphenolic redox manipulating phytochemicals

commonly display an aromatic core with 1,2-hydroxylgroups, which are found in hydroxychavicol and ChA, ora hydroxyl group and neighboring methyl ether like ineugenol and CHV (Fig. 5). These groups have been shownto act as an electron acceptor or hydrogen atom donor andquench the existing ROS and thus prevent the cell fromtransforming into a cancerous entity. When present inappropriate concentrations, these powerful phytochemicalsact as antioxidants. It has been well described throughoutthe literature that phenolic compounds exist as excellentelectron acceptors due to the resonance stabilization of theradical structure and an excellent hydrogen atom donor forsimilar stabilizationof the resultingoxyanion. Furthermore,

the electrophilic reactive oxygen quenchers like ChA andcurcumin contain a Michael acceptor enone system shownby the a-, b-unsaturated ketone and maintain the effectiveROS manipulating system of the dihydroxyl groups.

On the other hand, it is well studied that plant poly-phenols containing catechol and/or pyrogallolmoieties canalso exert pro-oxidant properties, by reducing iron (III) orcopper (II) ions that they chelate. Furthermore, the ortho-hydroxyphenoxy radical produced from the oxidation of acatechol/pyrogallolmoiety can also reactwith a second free-radical species, including 3O2, to afford oxidizing ortho-quinones and O2

�. (59). Because of these reactions, thecatecholic betel phenolic compounds like hydroxychavicoland ChA (Fig. 5) induce DNA breakage in the presence of3O2 and iron or copper species, thus leading to death.

The xenohormetic process thus fills the gaps in knowl-edge on the cancer preventative benefits of plant-basedphytochemicals in addition to their roles to kill transformedcancer cells. The xenohormesis phenomenon aids to com-prehend the basis of the chemopreventive potential of thesebetel phytochemicals that "prevent" carcinogenesis andintervene early on in themalignant transformation process.Thus, we believe that it is not unreasonable to include betelphytochemicals endowed with "magical" health imparting

Figure 5. A, structural comparisonof betel leaf phenolics with knownxenohormetic compounds likecurcumin and resveratrol suggeststhat the hydroxyl groups act aselectron acceptors or hydrogenatom donors and quench theexisting ROS, favoring axenohormetic response by betelleaf nutraceuticals. Catecholmoieties on betel phenolics arehighlighted within the red boxes.B, furthermore, free radicals areeliminated because of metalchelating and stabilizing propertiesof certain phenolic compounds,thus conferring them strongantioxidant activity.

Piper Betel Leaf: Anticancer Benefits

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powers in the armamentarium of the known "xenohor-metic" molecules.

In the light of these observations, we may rationalize thatin initiatedcells, amild stress inducedbybetel nutraceuticals,causes the activation of the Nrf2 circuit encouraging theexpression of endogenous antioxidants and other cytopro-tective genes, which generate a xenohormesis-mediated che-mopreventive response. Although extensive data from sev-eral in vivo studies demonstrate the chemopreventive efficacyof betel leaf and its constituents, the paucity of supportingclinical data demands an urgent need for strategic explora-tion of these effects upon daily consumption in humans.

Health in harmony: synergy among betelnutraceuticals

The complexity of phytochemicals in their natural formsin plant-based foods precludes a definitive conclusionabout their mechanisms of action. However, the existenceof synergistic interactions have been long known and linkedto the activity of whole foods. The chemotherapeutic andchemopreventive properties of betel leaf and its constitu-ents spur the need for examining and identifying the frac-tion and constituents thereof, which contribute to theremarkable efficacy.We have recently reported that the leastpolar fraction, F2, of betel leaf extract exhibited the highestantiproliferative activity when tested against human pros-tate cancer, PC-3 cells (20). F2 was identified to be consist-ing of hydroxychavicol andCHValongwithother unknownphytochemicals, and hydroxychavicol was found to be themajor contributor of betel leaf extract efficacy. Interestingly,this study suggested a possible synergy among F2 constitu-ents but additional in vivowork, including pharmacokineticevaluations, is warranted to draw conclusions on the poten-tial usefulness of the subfractions or single agents forchemopreventive or therapeutic goals.

Considering the potential synergistic interactions amongbetel leaf constituents and the remarkable in vivo tumorgrowth inhibitory dose of whole betel leaf extract in micebearing human prostate cancer (400 mg/kg body weight;ref. 20), correlations to human health benefits can beobtained. Allometric scaling calculations suggest that uponextrapolationofmicedata tohumans (60), the approximatehuman equivalent dose of whole betel leaf extract wasfound to be approximately 32 mg/kg body weight, whichtranslates to approximately 2.2 g for a 70-kg adult. Further-more, according to the United States Department of Agri-culture’s Food Guide pyramid (61), this dose can beobtained from approximately 41 g, or about one-fourthcup of fresh betel leaves, which can perhaps easily beincorporated in daily diet. However, detailed pharmacoki-netic investigations and pharmacodynamics analyses are

necessary before conclusions on dose extrapolations, die-tary incorporation, duration of consumption, etc., can beimplemented.

ConclusionAlthough the zeal and zest for discovering novel phar-

maceutical leads from plant extracts have dwindled inrecent years, the dominance of plants as superior sourcesof new drug discovery is unchallengeable. Exploiting thebounty of Mother Nature to identify and isolate valuablecancer-fighting agents from fruits, vegetables, and spices is apriority considering the increasing incidence of cancer inthe world population. In particular, food materials labeledas "generally recognized as safe" (GRAS) are appealingsources to identify xenohormetic molecules that offerhealth-promoting effects and that complement the chem-ical space of drugs. Nowonder the emergence of Foodinfor-matics, a new variant of ChemInformatics, will uncoverpotential applications of bioactive food chemicals usingcomputational approaches.

Piper betel, an exotic condiment, reported to be a treasureof bioactive phenolics, possesses great potential to fightagainst cancers of oral,mammary, prostate, skin, and gastricorigin. Much of these powers of betel leaf phytochemicalsremain unharnessed and call for extensive research to betterunderstand their mechanism(s) of action and clearlydemarcate their chemopreventive and chemotherapeuticroles. Through this review,wehave attempted to summarizethe advances in understanding the betel leaf action, itsconstituents, and their anti- and pro-oxidant nature, whichbear chemopreventive and chemotherapeutic ramifica-tions. We place into perspective the two seemingly inter-twined preventive and therapeutic activities by discussingthe physiologic difference in ROS levels in normal versuscancer cells and how this exposes an exploitable vulnera-bility of cancer cells, which can be appropriately "tuned" toenhance cancer cell selectivity to enable design of novelapproaches for the management of this insidious disease.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

AcknowledgmentsThe authors thank Bazla Shazad and Eric A. Owens for their contributions

to this work.

Grant SupportThis work was supported by grants from the National Cancer Institute at

the NIH (R00CA131489, R01 CA169127; to R. Aneja) and the AmericanCancer Society (121728-RSG-12-004-01-CNE).

Received October 11, 2013; revised December 19, 2013; accepted January9, 2014; published OnlineFirst January 21, 2014.

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