Review Article Advances in the Research and Development of ...downloads.hindawi.com/journals/ecam/2015/751348.pdf · Review Article Advances in the Research and Development of Natural

Review ArticleAdvances in the Research and Development of Natural HealthProducts as Main Stream Cancer Therapeutics

Pamela Ovadje1 Alessia Roma1 Matthew Steckle1 Leah Nicoletti1

John Thor Arnason2 and Siyaram Pandey1

1Department of Chemistry amp Biochemistry University of Windsor Windsor ON Canada2Department of Biology University of Ottawa Ottawa ON Canada

Correspondence should be addressed to Siyaram Pandey spandeyuwindsorca

Received 25 November 2014 Revised 7 March 2015 Accepted 8 March 2015

Academic Editor Kuzhuvelil B Harikumar

Copyright copy 2015 Pamela Ovadje et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Natural health products (NHPs) are defined as natural extracts containing polychemical mixtures they play a leading role in thediscovery and development of drugs for disease treatment More than 50 of current cancer therapeutics are derived from naturalsources However the efficacy of natural extracts in treating cancer has not been explored extensively Scientific research into thevalidity and mechanism of action of these products is needed to develop NHPs as main stream cancer therapy The preclinical andclinical validation of NHPs would be essential for this development This review summarizes some of the recent advancementsin the area of NHPs with anticancer effects This review also focuses on various NHPs that have been studied to scientificallyvalidate their claims as anticancer agents Furthermore this review emphasizes the efficacy of these NHPs in targeting the multiplevulnerabilities of cancer cells for a more selective efficacious treatment The studies reviewed here have paved the way for theintroduction of more NHPs from traditional medicine to the forefront of modern medicine in order to provide alternative saferand cheaper complementary treatments for cancer therapy and possibly improve the quality of life of cancer patients

1 History of Natural Health Products(NHPs) in Cancer

Natural health products (NHPs) and natural products (NPs)play a leading role in the discovery and the developmentof drugs for the treatment of human diseases Traditionalmedicines in the Native American Chinese and Indiancultures have utilized numerous natural products includingdozens of spices and plant extracts Scientific research into thevalidity of these traditional products has shown that manydo indeed have potent anticancer effects [1 2] An extractfrom the Mayapple Podophyllum peltatum was traditionallyused by Native Americans to combat skin cancers and othermalignant neoplasms as well as a host of other ailments Themajor component of this extract was podophyllotoxin whichwas the first in a series of effective anticancer agents calledpodophyllins [3] Likewise numerous natural products usedin traditional Indian Ayurvedicmedicine have been shown tohave strong anti-inflammatory and anticancer properties

Curcumin the active ingredient in turmeric has beenwidely studied for its anticancer properties Turmeric (Cur-cuma longa) itself was widely used in Ayurvedic medicineand the therapeutic benefits which are now attributed tothe presence of curcumin include the ability to suppresstumor growth in a wide variety of cancer types [4 5] Atotal of 27 anticancer drugs from 1940 to 2010 were obtainedfrom natural sources for instance actinomycin D pacli-taxel and vincristine now one of the most commonly usedchemotherapy agents in cancer treatment while topotecanHCl dexamethasone etoposide and even tamoxifen aremimics of natural products [1] (Figure 1) Camptothecinfound in extracts from Camptotheca acuminate and used intraditional Chinese medicine has been found to have antitu-mor activity and its derivatives topotecan and irinotecan areroutinely used to treat ovarian and colon cancers [6]

The discovery of the anticancer activities of so manytraditional medicines and natural products has been sup-ported by scientific evidence and validation This was in part

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015 Article ID 751348 12 pageshttpdxdoiorg1011552015751348

2 Evidence-Based Complementary and Alternative Medicine

36

9

4

10

0

28

13

50

11

9

4

22

4

39

126

9

1

25

8

Anticancer drugs (1940ndash2010)


NNDNBNM

SlowastSlowastNMSNMOthers

All drugs (1981ndash2010)

Figure 1 Sources of anticancer drugs from the 1940s to 2010 lowastNatural product (N) derived from a natural product usually a syntheticderivative (ND) Natural product ldquoBotanicalrdquo (NB) natural product mimic (NM) totally synthetic drug (S) made by total synthesis but thepharmacophore iswas from a natural product (Slowast)

successful due to the initiation of the Cancer ChemotherapyNational Service Center (CCNSC) in 1955 by the NationalCancer Institute (NCI) The mandate of this program was toscreen for antitumor agents on a larger scale by establishinga strict standardized protocol for testing potential anticancercompounds [7]

Since the 1980s research into the anticancer effects ofnatural products has yielded many promising results Forexample resveratrol a polyphenol present in grapes showspotential as both a preventative and an antitumor agent [8]

Similarly piperlongumine extracted from Piper longumselectively induces reactive oxygen species in cancerous cellsleading to apoptotic cell death [9] In the 1980s Bagshawe etal developed a novel use for natural products the antibody-directed enzyme-prodrug therapy (ADEPT) This techniqueused tumor-specific antibodies bound to an enzyme thatwould convert noncytotoxic prodrugs into their cytotoxicforms once in contact with the tumor [10 11] Many natu-ral products were successfully used as prodrugs includingdoxorubicin and Taxol [3] These earlier studies have paved

Evidence-Based Complementary and Alternative Medicine 3

the way for the introduction of more NHPs from traditionalmedicine to the forefront of modern medicine The scientificvalidation of these NHPs in terms of their efficacy safetyand mechanism of actions will seal their position in modernmedicine especially in the field of cancer research andtherapy

2 Current Trends in NHPResearch and Cancer

Even with all the incoming evidence herbal drugs andother NHPs and NPs are usually shunned during systemicchemotherapy because of herb-drug interaction and exag-geration of chemotherapy-related toxicity Current researchis focused on the development of new and more effectivechemotherapeutic agents that have little to no associatedtoxicity to the patient Lately this focus has been centered onNHPs and herbal formulations mainly in the form of plantsand other biological sources around the world NHPs havebeen used for centuries by a variety of cultural backgroundsfor a great number of illnesses some of which continuallyprovide newmedicinal applications and intriguing anecdotalevidence which merits further investigation Today thereare numerous natural health products that fall under theumbrella of traditional medicine such as the Indian herbsTulsi (Ocimum sanctum) Neem (Azadirachta indica) andAshwagandha (Withania somnifera) commonly known asIndian ginseng or winter cherry These herbs have shown anincredible diversity of treatments for diseases in both ancientandmodern times as well Ayurvedic medicine has been veryinformative in the introduction of numerous NHPs Tulsialso referred to as ldquoHoly Basilrdquo has in past decades beenstudied for its many health benefits which includes but is notlimited to treatments for bronchitis pain malaria asthmaarthritis cancer diabetes and numerousmicrobial infections[12 13] One study claims that it is primarily the phenoliccompound eugenol to which the health benefits of Tulsiare owed [12] however more recent research suggests thatthere is an additional range of compounds at work includingthe phytochemicals rosmarinic acid apigenin myretenalluteolin 120573-sitosterol and carnosic acid all of which havebeen shown to be valuable in the reduction of chemicallyinduced cancers through initiating apoptosis and maintain-ing antioxidative and antiangiogenic effects [14] On the samepage Neem leaves have been shown to possess a strikinglysimilar range of pharmacological effects to Tulsi and in onestudy is referred to as a ldquoliving pharmacyrdquo in itself [15] Thebenefits of Neem range from reductions in inflammationmicrobial infection progression of diabetes oxidative stresscancer proliferation and tumor development indicatingchemopreventive benefits Some of the active compoundswithin Neem are Azadirone Nimbidin Nimbolide and thePolysaccharides GIa and GIb [15 16] Ashwagandha hasbeen a staple in traditional Indian medicine for decadesand has been widely used owing to the various propertiesthat have been attributed to it Ashwagandha is proposedto have antioxidant anti-inflammatory anticancer antistressand adaptogenic properties [17 18] The extracts of this planthave been studied intensely to validate the claims that have

been the backbone of its use in ayurvedic medicine A recentstudy in 2013 showed the efficacy ofWithania extract againstmetastatic breast cancer The ethanolic extract of this plantwas efficient in preventing the invasion of breast cancer cellsin a spheroid invasion assay while inhibiting the metastasisof breast tumors to the lungs and lymph nodes in animalmodels [19] In Phase II clinical studies this herb was shownto promote ldquogeneral well-being of patientsrdquo when used incombination with chemotherapy as well as enhance thecytotoxicity of chemotherapy in breast cancer patients Thiscombination treatment led to an increase in the quality of lifeof the breast cancer patients in this study [18 20]

Another example of an NHP that has been used for cen-turies is the extract of dandelion a perennial weed known forits curative properties The dandelion species have been usedin many traditional and modern herbal medicinal systemsand this use has been documented all across the continentsVarious parts of this plant have been used in the treatment ofdifferent ailments with the root being used in gastrointestinaldiseases and the leaves as a diuretic and digestive stimulantThe whole plant has been taken as a cure for hepatitis andanorexia as well although some of the claims associated withthis weed have gone unsubstantiated [21 22] Some preclin-ical research on dandelion has introduced this plant withnumerous properties to the scientific community Researchhas shown the anti-inflammatory prebiotic antiangiogenicand antineoplastic properties of dandelion root [21] How-ever some studies do not agree with others leading to thepublication of conflicting reports on this NHPMore recentlystudies have shown selective efficacy of dandelion root extract(DRE) against several cancer cell types in a dose and timedependent manner The investigation of the mechanism ofaction of dandelion root extract in cancer cells is under studywith focus on the identification of the possible apoptoticpathway in which this extract is selective to cancer cells It hasbeen shown that DRE targets the death-receptor mediatedextrinsic pathway of apoptosis and its mechanism is depen-dent on the activation of caspase-8 [23ndash25] Overwhelmingscientific evidence with the aforementionedNHPs are pavingthe way for other NHPs especially in cancer treatment andintroducing these compounds and products as safe alterna-tives and effective contenders in the fight against cancer

3 Mechanistic Efficacy ofNHPs against Cancer

The different hallmarks of cancer and tumor cells includeevading growth suppression signals evading programmedcell death processes inducing angiogenesis and sustain-ing proliferative signaling to name a few [26 27] Thesehallmarks have been studied in great detail and thereforeprovide multiple means to target cancer cells selectively Thestudy of NHPs against cancer cells and xenograft modelshas therefore focused on identifying NHPs that can targetpathways that convey survival protection to cancer cells soas to selectively and effectively eradicate cancer cells Thisreview focuses on the role of NHPs in several pathwaysthat are involved in cancer including inflammation andinflammatory response oxidative stress and mitochondrial


response as well as receptor agonistsantagonists The studiesand results presented in this review are meant to highlightthe importance of NHPs in the targeting ofmultiple pathwaysthat are involved in cancer initiation and progression

31 Natural Health Products in Inflammation and Inflamma-tory Response in Cancer It is well-known that the inflamma-tory response is vital in living organisms for their protectionagainst foreignmatter Inflammationmore commonly occursin cases of infection and injury (acute inflammation) butin certain situations a more persistent deregulated andmaladaptive inflammation (chronic inflammation) can ariseThis chronic form of inflammation is usually associated withchronic diseases like cancer where there is exacerbation ofthe disease due to the prolonged inflammatory responseThis would lead to increased proliferation of the cancer cellsincreased angiogenesis and promotion of metastatic capa-bilities [28 29] making chronic inflammation a hallmark ofneoplastic transformation [30] Unlike acute inflammationthere is not much known about the processes and molecularpathways associated with chronic inflammation [29] how-ever there are anti-inflammatories available that might beable to target the inflammation and possibly the molecularpathways involved in order to reduce the extent of inflam-mation and possibly the unwanted effect of inflammationin chronic diseases like cancer One of the most commonexamples for the role of inflammation in cancer progressionhas been the use of nonsteroidal anti-inflammatory drugs(NSAIDs) and COX-2 specific inhibitors to reduce the riskof developing some cancers and preventing the mortalityassociated with those cancers [29] These NSAIDs and COX-2 inhibitors act by interfering with eicosanoid signaling andmetabolism suppressing the formation of tumors and actingas antioxidants and antiangiogenics

It has been found that there is a shared pathology betweencancer and inflammatory diseases which is displayed in thegene expression signatures for cancer and those for inflam-matory diseases [30]These findings suggest that targeting theinflammatory response is a potential way to target differentforms of cancer To combat unwarranted inflammation anti-inflammatories like aspirin ibuprofen and prednisone aremost commonly used despite their side effects [31] Alter-natively natural health products are used to heal a varietyof ailments including inflammation in a safe and effectivemannerThis prompts continual research into themechanismof natural anti-inflammatories as well as the discovery ofnew natural therapies Several phytochemicals includingcurcumin from turmeric and resveratrol from grapes areused partly due to their anti-inflammatory activity Theyinhibit inflammation by suppressing the activity of NF-120581Band possible STAT-3 [30 32]

Long pepper or Piper longum L has been used as both aspice and a therapy for a number of centuries Historicallyit was used as a topical treatment for muscle inflamma-tion but has shown efficacy in a number of diseases andconditions including diabetes cancer and obesity withouthaving any toxic effects [33] More recently the plant hasbeen studied as an anti-inflammatory agent for carrageenan-induced paw edema in rats In the study researchers found a

significant decrease in paw inflammation of rats treated withlong pepper indicating that long pepper suppressed acuteand subacute inflammation [34] In addition to this studyother work has been done on piperlongumine an importantcomponent of the long pepper fruit as a therapy againstatherosclerosis This study found that the anti-inflammatoryand antiplatelet aggregation properties of piperlongumineprevented artherosclerotic plaque formation inmice provingit to be a possible therapy for this inflammatory disease [2835] Furthermore in vitro studies in various cancer cell linesshowed the anticancer effect of piperlongumine in these cellswhere it was shown that this compound was able to target theoxidative stress response of these cells increase the levels ofreactive oxygen species (ROS) and activate the expression ofseveral key proapoptotic proteins This anticancer effect wasconfirmed in in vivo models of breast adenocarcinoma [9]Piperlongumine represents one of the compounds presentwithin long pepper that provides the anti-inflammatoryresponse from this plant however the effect of this compoundalone is significantly less than the whole plant extract inreducing inflammatory response [35 36]

In addition to long pepper and piperlongumine a naturalcompound found in grapes peanuts and berries known asresveratrol (3410158405-trihydroxystilbene) is a fat soluble com-pound that has also shown anti-inflammatory potentialResearchers became interested in elucidating the potentialhealth benefits of resveratrol when it was reported to bepresent in red wine which had previously been shown toreduce coronary heart disease by 20ndash30 [29 37] It hasbeen found that resveratrol can have a direct effect on theimmune response of the body and thus can be used as animmunomodulator in patients with inflammatory diseases[29] More specifically resveratrol suppresses the expressionof inflammatory biomarkers like TNF COX-2 iNOS andCRP preventing inflammation [30] Additionally resveratrolhas been shown to impede the activity of at least one type ofmatrix metalloproteinase enzymes which assist the invasionof normal tissue by cancer cells The anti-inflammatoryproperties of resveratrol have also been demonstrated in vitroStudies are inconclusive on whether or not high intakes ofresveratrol are effective in protecting against and preventingcancer in humans [38ndash40] however due to the ability ofthis compound to act as a potential therapeutic measure forcancer it is essential to pursue further studies on thisNHP Asnoted earlier due to the low bioavailability of resveratrol inhumans studies suggest that even high intakes of resveratrolmay not result in the same anticancer effectiveness that wasdemonstrated in cell culture [41]

Dandelion extracts have been found to have anti-inflammatory activity in some cancer cells [22] In a study byJeon and colleagues in 2008 an ethanolic extract of the wholeplant was shown to possess anti-inflammatory propertiesThis extract led to the downregulation of the production ofNO and COX-2 in activated macrophage cells [42]

These findings suggest a great potential for NHPs withanti-inflammatory activity in the fight against cancer Theability of these NHPs to target multiple pathways in inflam-mation and in cancer progression provides a potentiallymoreefficacious way to selectively target cancer cells


32 Natural Health Products in Oxidative Stress Responseand Mitochondrial Involvement in Cancer It has long beenknown that the mitochondria play a significant role in thecarcinogenesis and cancer progression [43ndash45] There area number of metabolic alterations that are associated withmitochondrial functions that can be used to differentiatecancer cell mitochondria from normal cell mitochondria Forinstance the activities of some enzymes that are required foroxidative phosphorylation are usually decreased in cancercells unlike normal cells It is however essential to note thatalthough there are a large number of differences between acancer cell and a normal cell mitochondria these differencesare not common to all cancer cells [44] Mitochondrialrespiration is coupled with the production of ROS andunder normal conditions these oxidative species are usuallyneutralized into harmless formsUnder abnormal conditionsthere is a corresponding increase in ROS and oxidative stresswhich leads to the mutations in both mitochondrial andnuclear DNA damage to proteins and lipids and resistanceto apoptotic induction Oxidative stress and the resultingmutations are typically at the basis of some malignantphenotype as can be seen in cancers [44 45] It has beenhypothesized that chronic inflammation (discussed above)is linked to oxidative stress and ultimately to carcinogenesis[44] Data from a study carried out in 1994 showed that therewas an increase in mitochondrial DNAmutations which aretypically associated with ROS production [46] Furthermorestudies have shown some commonly known antioxidants likevitamin E and some flavonoids present in natural extractscan inhibit inflammation thereby inhibiting carcinogenesisand progression of cancers [47 48]

A lot of research has gone into antioxidant mechanismsand the roles they play in tumor development Some ofthis work has provided better understanding of NHPs inoxidative stress response especially in cancer developmentand treatment There are increasing numbers of NHPs thatare involved in oxidative stress response One famous com-pound piperlongumine discussed above has been shown totarget and inhibit the endogenous oxidative stress responseof cancer cells leading to an increase in the levels of ROS anda corresponding increase in oxidative stress The inability ofthe cellsrsquo oxidative stress response to detoxify these reactiveoxygen entities led to the induction of apoptosis in cancercells This effect was countered by the presence of the antiox-idant N-acetylcysteine More importantly this effect on ROSgeneration and oxidative stress pathway targeting was notobserved in the noncancerous cells suggesting a dependenceon the oxidative stress response pathway in cancer cells[9] These results confirm what has been previously knowntargeting the mitochondria could provide a better selectivetarget in cancer cells [49] for more efficacious treatment

Some NHPs are proposed to contain both antioxidantand prooxidant properties Dandelion (Taraxacum officinale)flower ethanolic extract is considered one of such NHPs [50]The purpose of this study was to characterize the antioxidantproperties of dandelion flower extract (DFE) which wasattributed to the presence of luteolin and luteolin-7-glucosideInterestingly it was observed that higher concentrations ofthis extract had prooxidant effects in colon cancer cells This

is an important finding as it shows the versatility of NHPsunder different situations and conditions It is also essential tonote that the production of ROS can have both a proapoptoticand an antiapoptotic effect depending on the conditions ofthe cells [51] There is a growing body of evidence that provesthat ROS production acts not only as destructive agents butalso as chemical messengers [51] This information alongwith the fact that NHPs are so versatile further proves theimportance of NHPs as treatment options

Lots of studies have been carried out with otherNHPs forinstance epigallocatechin-3-gallate (EGCG) has been studiedfor its antioxidant capabilities for decades and treatmentwith this compound significantly slowed down the growth ofbreast cancer tumors in mice [52] Other nutraceuticals likeresveratrol (discussed above) also have beneficial claims inantioxidant therapy Several studies have shown that NHPsrich in flavonoids and phenolics play a significant role inoxidative stress response and concomitant use of NHPs withthese components increases the activities of the other NHPs[48 52 53]

There are a lot of characteristics attributed to curcuminand its role as an anticancer agent Curcumin from turmericis another natural compound that has both antioxidantand prooxidant characteristics and this capability has beenstudied in various cell culture models and confirmed in in-vivo studies [5 54 55] These studies definitely speak tothe versatility of NHPs and natural compounds in targetingmultiple cell pathways especially in the fight against cancer

Even with advances in NHP research we are still a longway from understanding the connections between some oftheseNHPs and oxidative stress especially in cancer researchIt is therefore essential to further investigate how NHPs areable to distinguish between different conditions and act inaccordance to both scavenge and induce the production ofradical oxygen species

33 Natural Health Products as Receptor Agonists and Antago-nists in Cancer Abnormal and excessive signal transductionis a commonhallmark of cancer cellsThis is in part due to theability of these cell types to upregulate the expression of bothreceptors and the ligands (usually growth factors) requiredto transmit downstream signals This ability thereby confershyperproliferative characteristics to cancer cells for instancethis is observed in aberrant Ras and myc signaling [56] Thistherefore suggests that a way to target cancer cells effectivelywill be to target the aberrant signaling pathways either byknocking down the expression of ligands andor receptorsor preventing signal transduction by introducing an antag-onist thus indicating the importance of NHPs as potentialanticancer agents Several NHPs have been reported to playan antagonistic role against several important receptors inthe aberrant signaling pathways in cancer cells Due to thepresence of many components in some of these NHPs it isnot surprising that one or more of these components couldtarget different receptors and signaling pathways

One particularly interesting class of compounds is thesesquiterpene lactones (SLs) found in an initial screen bythe National Cancer Institute (NCI) the same screeningthat led to the identification of Taxol [57] These SLs are


generally plant secondary metabolites and although almostexclusive to the Asteraceae plant family they can also befound in the Umbelliferae and Magnoliaceae families as wellThese compounds are worth further investigation for theirdevelopment as anti-inflammatory and selective anticanceragents [57] Owing to this ability extracts of plants highin SLs have been given considerable interest especiallyin cancer and inflammatory diseases [23ndash25 42 57] SLshave been shown to selectively target cancer stem cellsand a host of them has successfully proceeded to PhaseI and Phase II clinical trials Some common ones includeArtemisinin (Artemisia annua L) Thapsigargin (Thapsia)and Parthenolide (Tanacetum parthenium) and these havebeen successful in a lot of studies involving various typesof cancers laryngeal breast colorectal and non-small celllung carcinoma (Artemisinin) breast kidney and prostatecancers (Thapsigargin) and AML and lymph node cancers(Parthenolide) The activity of these SLs is mainly attributedin part to their ability to target cell surface transferrinreceptors (a distinct hallmark of rapidly proliferating cells)NF-120581B signaling (by disrupting the recruitment of I120581B kinasecomplex to the TNF receptor which is essential for tumorinitiation progression and resistance) and the angiogenesispathways by inhibiting human vein endothelial cell prolif-eration and vascular endothelial growth factor and receptorexpression [57 58] Antiangiogenic drugs have been of greatinterest especially in the field of cancer The generation ofnew blood vessels provides tumor cells with growth and sur-vival advantage as tumor cells depend on an adequate supplyof oxygen and nutrients for continued survival This increasein tumor vasculature also increases the chances of metastasisto distant sites Therefore finding antiangiogenic drugs thatcould not only inhibit angiogenesis but also decrease thechances of tumor metastasis is of utmost importance Theefficacy and benefits of SLs as antiangiogenics are proofthat this (angiogenesis) is an essential target in the fightagainst cancer More recently there have been increasingevidence for the role of NHPs as antiangiogenics especiallythose containing bioactive phytochemicals like sesquiterpenelactonesMoreover the fact thatmanyNHPs containmultiplebioactive phytochemicals makes them a viable source forreceptor agonists and antagonists There are many reports ofnatural health products with direct and indirect effects onangiogenesis see Table 1 [47 59ndash65]TheseNHPs act to targetthe different pathways involved in angiogenesis by decreasingthe expression of target proteins and receptors For instancethe epidermal growth factor and its corresponding receptorhave downstream effects on urokinase-type plasminogenactivator (uPA) which in turn can promote angiogenesisIn addition COX-2 and lipoxygenase (LOX-5) tend to havestimulatory effects on cancer progression and angiogenesisand increase in COX-2 expression is associated with aprogression to invasive phenotypes in certain cancer typesFurthermore vascular endothelial growth factor (VEGF)is associated with increased proliferation and migration ofendothelial cells and an increase in the expression of met-alloproteinases (MMP) leading to increased vascularizationwithin a tumor that promotes metastatic capabilities Thesesuggest that NHPs and NPs that can target the expression of

Table 1 Natural health products that target the angiogenesispathways

NHPsNPs Target (decrease)Artemisia annua (artemisinin) VEGFKDR

Camellia sinensis (epigallocatechin) VEGFprotein kinase C

Chrysobalanus icaco (methanolextract)

Curcuma longa (curcumin)

MMP-29VEGFbFGFCD13 (aminopeptidaseN)

Ginkgo biloba (ginkgolide B) VEGF

Magnolia obovata (honokiol) PGDFTGF 120573

Polygonum cuspidatum (resveratrol) MMP-2VEGF

QuercetinCOX-2lipoxygenase-5 enzymesEGFR

Scutellaria baicalensis (baicalin andbaicalein)

VEGFbFGF12-lipoxygenase activityMMP

Silybum marianum (silymarin) VEGFViscum album (lectins) VEGFSqualus acanthias (dogfish liversqualamine) HER2

Soy isoflavones (genistein daidzein) EGFR (HER1)Aloe barbadensis (aloe vera leaf andpulp extracts) HER2neu

Omega-3 fatty acids (eicosapentaenoicacid docosahexaenoic acid)

COX-2lipoxygenase-5 enzymesEGFR

Ocimum sanctum (carnosol ursolicacid)

COX-2NF-120581Bseveral tyrosine kinasesEGFR

Rosmarinus officinalis (carnosol andursolic acid)


Zingiber officinale (6-gingerol) COX-2NF-120581B

key players in angiogenesis (such as those listed in Table 1) areviable options for the treatment of cancer

Several other receptors play a role in the progression ofcancers especially the estrogen (ER) and androgen receptors(AR) which are seen in breast and prostate cancers [66]There are two main isoforms of the ER the alpha (ER-120572) and the beta (ER-120573) isoform which have been shownto play opposing roles in the initiation and progression ofbreast cancers the alpha isoform promotes tumor formationand progression while the beta isoform takes on the roleof a tumor suppressor [67] This information indicates that


these receptors are another viable option in the attempts totarget cancer cell and tumor progression Emerging researchsuggests that the activation of the AR is able to inhibit breastcancer progression [67] and its expression is a significantprognostic marker in estrogen receptor positive breast can-cers [68]This suggests that downregulating the expression ofthe ER andor activating the downstream signaling of the ARcanbe essential in the fight against breast cancer however ARplays a significant role in the development and progressionof therapy-resistant prostate cancer [69 70] indicating thatactivation of AR to treat breast cancer will have dire effectson the prostate and suggesting that a focus on ER antagonistswould be a more efficacious option Lately more research isgoing into identifying NHPs and NPs that can target thesereceptors leading to a decrease in their downstream activity

Perhaps the most common example of an ER antagonistis tamoxifen which is used especially for hormone-receptivebreast cancer treatment Recent studies have shown thatadministration of soy isoflavones such as genistein anddaidzein can have an effect on the efficacy of tamoxifenSome studies suggest that some isoflavones (genistein) canincrease the potency of tamoxifen in ERminus breast cancer cellsand have the opposite effect in ER+ cells while others indicatethat daidzein in combination with tamoxifen has increasedprotection against both ER+ and ERminus breast carcinomas [71]This indicates that the use of NHPsNPs must be used withcaution and advocates a necessity for scientific validation ofthe mechanism of actions indications and contraindicationsof NHPsNPs to ensure safety and lack of toxicity associatedwith the administered treatment

Several NHPs have been shown to induce different typesof programmed cell death including apoptosis necrosisand autophagy in cancer cells some in a selective mannerHowever understanding the mechanism of action of theseNHPs sometimes proves difficult as themultiple componentstend to have multiple targets This has led to increasingmechanistic studies into effective NHPs and some of thesestudies have identified active NHPs with receptor antagonis-tic activities For instance withaferin A a naturally occurringbioactive component isolated from Withania somnifera wasshown to knock down the expression of ER-120572 but not ER-120573 leading to its role in chemoprevention and apoptosisinduction [72]

As mentioned earlier several compounds found in soyisoflavones have significant anticancer activity with genisteinand daidzeinrsquos ability to target HER2neu and EGFR toinhibit angiogenesis [59] Several studies have also shownthat these compounds are able to target the ER however notwith great affinity Another study showed that one of thesecompounds daidzein is converted to corresponding Equolby gut microflora There are two isoforms of this compoundR-Equol with a moderate binding preference for ER-120572 andS-Equol with a strong binding preference for ER-120573 and bothof these have much higher binding affinities for the ERs thantheir biosynthetic precursor compound daidzein [73] Thissuggests not only that NHPs contain bioactive componentsthat could have multiple targets but also that this bioactivecomponents could act as precursor compounds for othercompounds with even better activities against the different

targets as seen with the ER affinities of daidzein and its latercompounds

Another source of bioactive components is the longpepper from the genus Piper (Piperaceae) These speciesare one of the most widely used NHP worldwide withmany biologically active secondary compounds having beenidentified in this species The most common compoundidentified in piper spp is piperlongumine (PL) Scientificevidence has shown the anticancer efficacy of PL by targetingthe ROS stress response mechanism in cancer cells [9]Further studies have also shown the ability of PL to targetreceptors including the PDGF receptors for the inhibitionof angiogenesis and more importantly treatment with thiscompound led to the depletion of androgen receptor inprostate cancer cells through a proteasome-mediated ROSdependent pathway [74 75] This not only suggests the roleof this NP as a receptor antagonist but also provides alink between oxidative stress and receptor targeting for analternative path to cancer cell specific targeting proving thisusefulness of NHPs and NPs in the fight against cancer

Aside from receptors involved with increased geneexpression and cell growth and proliferation death receptorsare also key players in normal and cancer cell growth andsurvival These receptors belong to the tumor necrosis factor(TNF) superfamily of receptors that play a role in signalingcell death and survival pathways and include TNFR1TNF-120572 FasRFasL and TNF-related apoptosis inducing ligandTRAILTRAIL-R1 (DR4) or TRAILTRAIL-R2 (DR5) [7677]These death receptors are ubiquitously and constitutivelyactive in tissue types in the human body with some tissueshaving a higher expression than others The main differencebetween normal tissues and tumor tissues is the increasedexpression of the noncanonical prosurvival signaling ofthese receptors in tumor cells for instance many tumorcells overexpress TRAIL-R3 and TRAIL-R4 (decoy receptorsDcR1 and DcR2) with truncated cytoplasmic death domainsthat prevent the transmission of signals following bindingof ligand to receptor Also there is evidence that implicatesseveral noncytotoxic pathways that are mainly facilitated bythe activation of NF-120581B and MAPK pathways through theactivation of RIP kinase [77 78]This indicates that the deathreceptors provide another target in the fight against cancerFor instance over the years TRAIL and other ligands againstTRAIL-R1R2 have generated considerable interest due tothe selectivity of these ligands towards cancer cells with littleto no toxicity to noncancerous cells [77] suggesting theirusefulness as cancer therapies

Studies have shown that several NHPs are able to targetdeath receptor signaling pathways again confirming theirusefulness as potential anticancer agents The selective anti-cancer efficacy of dandelion root extract has been attributedto its ability to induce death-receptor mediated extrinsicapoptosis in cancer cells selectively [23ndash25] and a loss ofthis activity was observed in cells with a dominant negativeFas-Associated Death Domain (FADD) [24] This knack fordeath receptor targeting can be attributed to the presenceof sesquiterpene lactones [58] and the suppression of cellu-lar FLICE-like inhibitory protein (cFLIP) which is highlyexpressed in several cancer cell types including pancreatic


cancer cells by the triterpene lupeol [79] This compoundis one of the bioactive components of dandelion extracts[23 80] This inhibition of cFLIP has been shown to renderTRAIL-resistant cancer cells sensitive to TRAIL therapy [79]A derivative of resveratrol was found to induce FADD-dependent apoptosis in several human leukemia cells sig-nificantly higher than resveratrol by itself This dependenceon FADD was not contingent on the expression of FasTRAIL or TNF-120572 [81] suggesting that even in the absenceof ligand andor receptor some NPs could still activate deathreceptor extrinsic pathway to selectively target cancer cells toapoptosis

Taxanes (eg paclitaxel and docetaxel) isolated fromTaxus are effective as cytotoxic agents as they target and sta-bilize the microtubules and prevent their depolymerizationthereby interfering with normal cell functions and induceapoptosis Further studies on the mechanism of taxanesindicate that these compounds can induce the expression ofTNF-120572 and decrease the expression of certain TNF receptors[52] where prodeath TNFR1 expression was decreased andprosurvival TNFR2 expression was increased [82]This couldsuggest a way by which cancer cells develop resistance totaxane treatment although further investigation into thismechanism is still required as TNFR2 is also implicated incell death signaling [82]

Curcumin discussed in previous sections of this reviewhas shown significant anticancer activity in several cancercells with the ability to target multiple signaling pathwaysNot only does it antagonize cell surface receptors like theepidermal growth factor receptor (EGFR) but it has also beenshown to induce apoptosis in humanmelanoma cells throughthe activation of the Fas receptor and subsequent activation ofcaspase-8 [83] proving itself a worthy opponent in the fightagainst cancer progression

These indications of the roles ofNHPs andNPs as agonistsand antagonists of receptors for the selective targeting ofcancer cells to the process of cell death give further validationto the use of these products as safer alternatives to currentcancer treatments However these examples also indicate thatthere is a lot of work that is required to further understandhow these NHPsNPs are able to recognize the aberrantsignaling system in cancer cells and exploit these differencesand vulnerabilities although these studies provide a steppingstone for future validation of NHPs in the mechanistic vali-dation of selective targeting of cancer cells for programmedcell death processes

4 Characterization of Complex NaturalHealth Products Fractionation andMetabolomics Profiling of Active Fractions

NHPs are usually complexmixtures that containmany bioac-tive substances Dosage forms are difficult to characterizeas traditional preparation dosage and usage do not accountfor the presence of the various bioactive components It istherefore imperative that identification of pharmacologicallyactive ingredients within any NHP is carried out As men-tioned earlier in-vitro studies of dandelion root extract have

Table 2 Compounds identified in standardized GMP decoction ofdandelion roots by UPLC MS QTOF

Compound Molecularformula

Monoisotopicmass

4-Hydroxybenzoic acid C7H6O3 1380316941Sucrose C12H22O11 3421162116Vernoflexuoside C21H28O8 4081784179Pollinastanol C28H48O 4003705162Austricin C15H18O4 2621205091Lycoperodine 1 C12H12N2O2 216089877611-beta 13-dihydrolactucin C15H18O5 2781154237Cichorioside C C21H32O9 4282046326Taraxafolide C21H28O10 4401682471Sonchuside A C21H32O8 412209718Annuolide D C15H20O3 2481412445Notoserolide A C21H28O9 4241733325Taraxacin C15H14O3 2420942943Taraxinic acidbeta-D-glucopyranosyl ester C21H28O9 4241733325

shown its efficacy in various cancer cell lines giving it thepotential to be developed as an anticancer agent Dandelionroot is a very complex biological material containing manybioactive substances and there are several ways of preparingdandelion roots for consumption Infusions or decoctionsof dry roots have been used by cancer patients in casereport of individuals who have gone into remission Toprovide a reproducible dosage form a highly standardizeddecoction of roots can be prepared and lyophilized for clinicaland phytochemical evaluation The resulting standardizedproduct from dandelion root is a brown powder which wasreconstituted inwater and polysaccharides precipitated by 1 1addition of ethanol using a procedure adapted from purifica-tion of ginseng polysaccharidesThe resulting polysaccharidefraction was obtained by centrifugation and represents 20by weight of the product This material is mostly inulin anondigestible polymer of glucose rather than starch foundas a storage product in many plants As well small amount ofplant cell wall derived hemicellulose and pectin are extractedWhile these substances have yet to be assayed inulin isgenerally considered to be relatively inert while cell wallderived polysaccharidesmay have immunostimulant activityas has been found for ginseng acidic polysaccharides that actvia toll-like receptorsThe remaining 80 of the products aresmall molecular weight compounds which were subjectedto metabolomic analysis with a Waters Xevo UPLC MSQTOF This fraction is highly complex and 91 compoundswere selected for identification based on published literatureIdentification of 14 compounds was achieved by elementalcomposition and monoisotopic mass observed followingelectrospray ionization The compounds identified are foundin Table 2 and except for sucrose they represent knownor potentially bioactive phytochemicals Many of the com-pounds are sesquiterpene lactones such as taraxifolide orphenolic glycosides such as cichorioside


Using standard pharmacognosy methods for the identifi-cation of active principles identification of active principlescan be achieved These studies provide the backbone that isrequired to ensure standardization of NHPs that could bebeneficial in the treatment of diseases especially cancer

In conclusion antiproliferation activity has been foundin both (water) polar and nonpolar (ethanolic) fractions ofmanyNHPs for instance with dandelion root extracts whichcontain sesquiterpenes phenolics and triterpenes [42 50]As with many medicinal plants activity may be connectedwith the joint action of several compounds rather than asingle active molecule Further work is required to assaythe antiproliferative activity of the identified compounds andexamine their combined activity

5 Combinatorial Activity ofNatural Health Products

With all the evidence put forward in the previous sections ofthis review it stands to reason that the multiple componentspresent within an NHP play a role in and are responsiblefor the selective efficacy of these NHPs against cancer cellsin vitro and in xenograft models It is therefore essentialto carry out further studies on a whole extract of an NHPto determine if it has better efficacy as a whole or if theisolated and characterized compounds provide the efficacyand selectivity we require for cancer treatment Studies onwithania somnifera have led to the identification of severalbioactive components (eg the efficacy of withaferin A)however studies including clinical trials have shown thatthe effect of singular compounds found within this extractdoes not compare to the benefits of using the whole extractespecially as an anticancer agent [17ndash20] Unpublished datawith some of the identified bioactive phytochemicals indandelion root extracts also indicate that that the efficacy ofthe whole extract or a combination of two or more bioactivecomponents is better than each of the single compoundsthemselves Traditional medicine practice has been knownto combine multiple NHPs for better advantage [60 84]These combinations might also prove to be more selectivethan single component treatments As seenwithmost of theseNHPs that are able to target multiple signaling pathwaysthese characteristics are mainly due to the presence of mul-tiple components It is possible that the precise combinationsof these components prevent or decrease toxicity associatedwith treatment while proving to be more efficacious atlower treatment doses due to the synergistic activity ofthe different compounds Hence NHPs appear to providean alternative to current chemotherapy by providing saferlower dose treatment options or providing a source of NPsthat can be garnered for cancer treatment Furthermore acombination of two ormoreNHPsmight increase the efficacyand selectivity while reducing the chances of developingresistance to treatment as these multiple NHPs could targeteven more pathways and be used at even lower doses

Extensive scientific validation will be required to deter-mine the efficacy safety and mechanism of action of thecombined treatment options for the effective treatment of

cancer The effectiveness of these NHPs may be increasedwhen multiple agents are used in optimal combinations

6 Health Agencies and Regulatory BodiesInvolved with Natural Health Products

The whole purpose of the scientific validation of NHPsagainst diseases especially cancer is to provide awareness forthese NHPs and NPs that have been used for centuries invarious traditional medicines The scientific studies carriedout provide the necessary evidence regarding the efficacyof these NHPs their indications and contraindications andinformation on their safe and effective use In Canada HealthCanada is the governing agency for the introduction ofdrugs and NHPs to the public with divisions completelydedicated to NHPs the Natural Health Product Directorate(NHPD) and the Therapeutic Product Directorate (TPD)These divisions were generated to assist and ensure thatCanadians have access to NHPs that are ldquosafe effectiveand of high quality while respecting freedom of choice andphilosophical and cultural diversityrdquo Regulations for NHPscame into effect in 2004 and take into account their uniquenature and characteristics At the end of 2012 the NHPDpublished information that outline how NHPs are assessedwith a focus on health claims the use of risk informationand the use of NHPs in combination these include the ldquoPath-way for Licensing NHPs Making Modern Health ClaimsrdquoldquoPathway for Licensing NHPs making Traditional HealthClaimsrdquo and ldquoQuality of Natural Health Products Guiderdquowhich summaries the requirement for standardization of highquality NHPs Even after clinical trials and progression tothe market Health Canada continues to collect informationon adverse reaction reports for NHPs to track and analyzethese reaction reports for NHP use through the CanadaVigilance Program and other regulatory agencies like theWorld Health Organization (WHO) This allows constantmonitoring of NHPs to ensure continuous safety and efficacyassociated with these forms of treatment More informationon application to Health Canada and requirements involvedin getting anNHP to themarket can be found at their websitehttpwwwhc-scgccadhp-mpsprodnaturindex-engphp

In the United States the Food and Drug Administration(FDA) is the agency in charge of regulating the productionand provision of NHPs to the public NHPs are referred to ascomplementary and alternative medicine (CAM) which aredivided into 5 main domains

(a) whole medical systems Ayurveda homeopathicmedicine and traditional Chinese medicine (TCM)This is the most common domain of NHPsCAMswhich requires vigorous reviews and validation by thescientific community

(b) mind-body medicine meditation prayer and cre-ative therapies such as dance

(c) biologically based practices with herbs foods vita-mins and dietary supplements

(d) manipulative and body-based practices chiropracticand osteopathic manipulation and massage


(e) energy medicine including therapeutic touch

These domains undergo the same levels of rigorous reviewas described in the Health Canada review aspect above Moreinformation on application to the FDA and their require-ments can be found at their website httpwwwfdagovregulatoryinformationguidancesucm144657htm

These regulatory agencies ensure that health claims madeby traditional medicine have scientific validations for anec-dotal evidence presented for centuries They ensure properstandardizations involved in the production and usage ofNHPsNPsCAMs tomaximize the benefits of these productsand medicines

7 Significance and Conclusions

The toll of cancer on the human body and the society as awhole indicates a serious need for a better selective effectiveand cheapermode of treatment Natural health products holda great potential to provide nontoxic alternatives for the treat-ment of cancer More importantly NHPs as a complex poly-chemical mixture of pharmacologically active compoundsmay target multiple vulnerabilities of cancer cells withouttoxicity to the noncancerous cells The complete scientificand clinical evaluation of the potential NHPs are essen-tial to bring these products tomainstreamcancer therapies inorder to provide alternative safer and cheaper complemen-tary treatments for cancer therapy and possibly improve thequality of life of cancer patients With the health regulatoryagencies including Health Canada and the FDA providingthe required regulatory framework for the development ofNHPs for therapeutic purposes the future will see the growthand expansion ofmany cancer-selectiveNHPs inmainstreamcancer treatment

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to acknowledge the various con-tributions from the following groups and individuals theCouvillon family the Lotte amp John Hecht Memorial Foun-dation the Knights of Columbus Chapter 9671 The PajamaAngels The Seeds4Hope Windsor Essex County CancerCentre Foundation and the Jesse amp Julie Rasch FoundationThe work that the authors do is a direct result of the never-ending support they receive

References

[1] D J Newman and G M Cragg ldquoNatural products as sourcesof new drugs over the 30 years from 1981 to 2010rdquo Journal ofNatural Products vol 75 no 3 pp 311ndash335 2012

[2] A Ganesan ldquoThe impact of natural products upon moderndrug discoveryrdquo Current Opinion in Chemical Biology vol 12no 3 pp 306ndash317 2008

[3] J Mann ldquoNatural products in cancer chemotherapy pastpresent and futurerdquoNature ReviewsCancer vol 2 no 2 pp 143ndash148 2002

[4] B B Aggarwal H Ichikawa P Garodia et al ldquoFrom traditionalAyurvedic medicine to modern medicine Identification oftherapeutic targets for suppression of inflammation and cancerrdquoExpert Opinion onTherapeutic Targets vol 10 no 1 pp 87ndash1182006

[5] B B Aggarwal Y-J Surh and S Shishodia EdsTheMolecularTargets andTherapeutic Uses of Curcumin inHealth andDiseasevol 595 Springer Boston Mass USA 2007

[6] T Efferth P C H Li V S B Konkimalla and B Kaina ldquoFromtraditional Chinesemedicine to rational cancer therapyrdquoTrendsin Molecular Medicine vol 13 no 8 pp 353ndash361 2007

[7] V T deVita Jr and E Chu ldquoA history of cancer chemotherapyrdquoCancer Research vol 68 no 21 pp 8643ndash8653 2008

[8] R Lu and G Serrero ldquoResveratrol a natural product derivedfrom grape exhibits antiestrogenic activity and inhibits thegrowth of human breast cancer cellsrdquo Journal of Cellular Physio-logy vol 179 no 3 pp 297ndash304 1999

[9] L Raj T Ide A U Gurkar et al ldquoSelective killing of cancercells by a small molecule targeting the stress response to ROSrdquoNature vol 475 pp 231ndash234 2011

[10] K D Bagshawe ldquoAntibody directed enzymes revive anti-cancerprodrugs conceptrdquo British Journal of Cancer vol 56 no 5 pp531ndash532 1987

[11] K D Bagshawe L S K Sharma C J Springer and G TRogers ldquoAntibody directed enzyme prodrug therapy (ADEPT)A review of some theoretical experimental and clinical aspectsrdquoAnnals of Oncology vol 5 no 10 pp 879ndash891 1994

[12] P Prakash andNGupta ldquoTherapeutic uses ofOcimum sanctumLinn (Tulsi) with a note on eugenol and its pharmacologicalactions a short reviewrdquo Indian Journal of Physiology andPharmacology vol 49 no 2 pp 125ndash131 2005

[13] P Pattanayak P Behera D Das and S Panda ldquoOcimum sanc-tum Linn A reservoir plant for therapeutic applications anoverviewrdquo Pharmacognosy Reviews vol 4 no 7 pp 95ndash1052010

[14] M S Baliga R Jimmy K RThilakchand et al ldquoOcimum Sanc-tum L (Holy Basil or Tulsi) and its phytochemicals in the pre-vention and treatment of cancerrdquo Nutrition amp Cancer vol 65supplement 1 pp 26ndash35 2013

[15] S E Atawodi and J C Atawodi ldquoAzadirachta indica (neem)a plant of multiple biological and pharmacological activitiesrdquoPhytochemistry Reviews vol 8 no 3 pp 601ndash620 2009

[16] T Fujiwara E Sugishita T Takeda et al ldquoFurther studieson the structure of polysaccharides from the bark of Meliaazadirachtardquo Chemical and Pharmaceutical Bulletin vol 32 no4 pp 1385ndash1391 1984

[17] L-C Mishra B B Singh and S Dagenais ldquoScientific basis forthe therapeutic use of Withania somnifera (ashwagandha) areviewrdquo Alternative Medicine Review vol 5 no 4 pp 334ndash3462000

[18] B M Biswal S A Sulaiman H C Ismail H Zakaria and KI Musa ldquoEffect of Withania somnifera (Ashwagandha) on thedevelopment of chemotherapy-induced fatigue and quality oflife in breast cancer patientsrdquo Integrative Cancer Therapies vol12 no 4 pp 312ndash322 2012

[19] Z Yang A Garcia S Xu et al ldquoWithania somnifera rootextract inhibits mammary cancer metastasis and epithelial tomesenchymal transitionrdquo PLoS ONE vol 8 no 9 Article IDe75069 2013


[20] B M Biswal A M Sulaiman H C Ismail H Zakaria MI Jalil Abdul and K I Muhammad ldquoAOS14 Phase II clinicalstudy of combination chemotherapy with herbWithania somni-fera(ashwagandha) in breast cancerrdquo European Journal of Can-cer vol 48 supplement 4 pp S8ndashS9 2012

[21] E Yarnell and K Abascal ldquoDandelion (Taraxacum officinaleand T mongolicum)rdquo Integrative Medicine vol 8 no 2 pp 34ndash38 2009

[22] K Schutz R Carle andA Schieber ldquoTaraxacum-a review on itsphytochemical and pharmacological profilerdquo Journal of Ethno-pharmacology vol 107 no 3 pp 313ndash323 2006

[23] S Pandey S J Chatterjee P Ovadje M Mousa and C HammldquoThe efficacy of dandelion root extract in inducing apopto-sis in drug-resistant human melanoma cellsrdquo Evidence-BasedComplementary and Alternative Medicine vol 2011 Article ID129045 11 pages 2011

[24] P Ovadje C Hamm and S Pandey ldquoEfficient induction ofextrinsic cell death by dandelion root extract in human chronicmyelomonocytic leukemia (CMML) cellsrdquoPLoSONE vol 7 no2 Article ID e30604 2012

[25] P Ovadje M Chochkeh P Akbari-Asl C Hamm andS Pandey ldquoSelective induction of apoptosis and autophagythrough treatment with dandelion root extract in human pan-creatic cancer cellsrdquo Pancreas vol 41 no 7 pp 1039ndash1047 2012

[26] DHanahan andRAWeinberg ldquoThehallmarks of cancerrdquoCellvol 100 no 1 pp 57ndash70 2000

[27] D Hanahan and R AWeinberg ldquoHallmarks of cancer the nextgenerationrdquo Cell vol 144 no 5 pp 646ndash674 2011

[28] I Tabas and C K Glass ldquoAnti-inflammatory therapy in chronicdisease challenges and opportunitiesrdquo Science vol 339 no 6116pp 166ndash172 2013

[29] A Mantovani P Allavena A Sica and F Balkwill ldquoCancer-related inflammationrdquo Nature vol 454 no 7203 pp 436ndash4442008

[30] V N Sumantran and G Tillu ldquoCancer inflammation andinsights from ayurvedardquo Evidence-Based Complementary andAlternative Medicine vol 2012 Article ID 306346 11 pages2012

[31] A Viljoen N Mncwangi and I Vermaak ldquoAnti-inflammatoryiridoids of botanical originrdquo Current Medicinal Chemistry vol19 no 14 pp 2104ndash2127 2012

[32] Y-J Surh K-S ChunH-H Cha et al ldquoMolecularmechanismsunderlying chemopreventive activities of anti-inflammatoryphytochemicals Down-regulation of COX-2 and iNOSthrough suppression of NF-120581B activationrdquoMutation ResearchmdashFundamental and Molecular Mechanisms of Mutagenesis vol480-481 pp 243ndash268 2001

[33] S Kumar J Kamboj and S Sharma ldquoOverview for variousaspects of the health benefits of Piper Longum Linn Fruitrdquo Jour-nal of Acupuncture and Meridian Studies vol 4 no 2 pp 134ndash140 2011

[34] M Kumari B K Ashok B Ravishankar T N Pandya and RAcharya ldquoAnti-inflammatory activity of two varieties of Pippali(Piper longum Linn)rdquo AYU vol 33 no 2 pp 307ndash310 2012

[35] M Iwashita N Oka S Ohkubo M Saito and N NakahataldquoPiperlongumine a constituent of Piper longum L inhibitsrabbit platelet aggregation as a thoboxane A(2) receptor antag-onistrdquo European Journal of Pharmacology vol 570 no 1ndash3 pp38ndash42 2007

[36] G Vedhanayaki G V Shastri and A Kuruvilla ldquoAnalgesic acti-vity of piper longum linn Rootrdquo Indian Journal of ExperimentalBiology vol 41 no 6 pp 649ndash651 2003

[37] K B Harikumar and B B Aggarwal ldquoResveratrol a multitar-geted agent for age-associated chronic diseasesrdquo Cell Cycle vol7 no 8 pp 1020ndash1035 2008


[39] B B Aggarwal A Bhardwaj R S Aggarwal N P Seeram SShishodia and Y Takada ldquoRole of resveratrol in prevention andtherapy of cancer preclinical and clinical studiesrdquo AnticancerResearch vol 24 no 5 pp 2783ndash2840 2004

[40] C A de la Lastra and I Villegas ldquoResveratrol as an anti-inflam-matory and anti-aging agent mechanisms and clinical implica-tionsrdquoMolecular Nutrition and Food Research vol 49 no 5 pp405ndash430 2005

[41] L E Donnelly R Newton G E Kennedy et al ldquoAnti-inflam-matory effects of resveratrol in lung epithelial cells molecularmechanismsrdquoAmerican Journal of Physiology LungCellular andMolecular Physiology vol 287 no 4 pp L774ndashL783 2004

[42] H-J Jeon H-J Kang H-J Jung et al ldquoAnti-inflammatoryactivity ofTaraxacum officinalerdquo Journal of Ethnopharmacologyvol 115 no 1 pp 82ndash88 2008

[43] J S Modica-Napolitano M Kulawiec and K K Singh ldquoMito-chondria and human cancerrdquo Current Molecular Medicine vol7 no 1 pp 121ndash131 2007

[44] G Kroemer ldquoMitochondria in cancerrdquo Oncogene vol 25 no34 pp 4630ndash4632 2006

[45] C Frezza and E Gottlieb ldquoMitochondria in cancer not justinnocent bystandersrdquo Seminars in Cancer Biology vol 19 no1 pp 4ndash11 2009

[46] C W Birky Jr ldquoRelaxed and stringent genomes why cytoplas-mic genes donrsquot obeymendelrsquos lawsrdquo Journal of Heredity vol 85no 5 pp 355ndash365 1994

[47] SM Sagar D Yance and R KWong ldquoNatural health productsthat inhibit angiogenesis a potential source for investigationalnew agents to treat cancermdashpart 1rdquo Current Oncology vol 13no 1 pp 14ndash26 2006

[48] K I Park H S Park A Nagappan et al ldquoInduction of the cellcycle arrest and apoptosis by flavonoids isolated from KoreanCitrus aurantium L in non-small-cell lung cancer cellsrdquo FoodChemistry vol 135 no 4 pp 2728ndash2735 2012

[49] G G M DrsquoSouza M A Wagle V Saxena and A ShahldquoApproaches for targeting mitochondria in cancer therapyrdquoBiochimica et Biophysica Acta vol 1807 no 6 pp 689ndash696 2011

[50] C Hu and D D Kitts ldquoAntioxidant prooxidant and cytotoxicactivities of solvent-fractionated dandelion (Taraxacum offici-nale) flower extracts in vitrordquo Journal of Agricultural and FoodChemistry vol 51 no 1 pp 301ndash310 2003

[51] H U Simon A Haj-Yehia and F Levi-Schaffer ldquoRole of reac-tive oxygen species (ROS) in apoptosis inductionrdquo Apoptosisvol 5 no 5 pp 415ndash418 2000

[52] S Nobili D Lippi E Witort et al ldquoNatural compounds forcancer treatment and preventionrdquo Pharmacological Researchvol 59 no 6 pp 365ndash378 2009

[53] C Pereira L Barros M Vilas-Boas and I C F R FerreiraldquoPotentiating effects of honey on antioxidant properties oflemon-flavoured black teardquo International Journal of Food Sci-ences and Nutrition vol 64 no 2 pp 230ndash234 2013

[54] M N A Mandal J M R Patlolla L Zheng et al ldquoCurcuminprotects retinal cells from light-and oxidant stress-induced celldeathrdquo Free Radical Biology amp Medicine vol 46 no 5 pp 672ndash679 2009


[55] K S Parvathy P S Negi and P Srinivas ldquoAntioxidant antimu-tagenic and antibacterial activities of curcumin-120573-diglucosiderdquoFood Chemistry vol 115 no 1 pp 265ndash271 2009

[56] D J Kroll ldquoNatural compounds in cancer therapy promisingnontoxic antitumor agents from plants and other naturalsourcesrdquo Journal of Natural Products vol 64 no 12 pp 1605ndash1606 2001

[57] A Ghantous H Gali-Muhtasib H Vuorela N A Saliba andN Darwiche ldquoWhat made sesquiterpene lactones reach cancerclinical trialsrdquoDrugDiscovery Today vol 15 no 15-16 pp 668ndash678 2010

[58] S Zhang Y-K Won C-N Ong and H-M Shen ldquoAnti-can-cer potential of sesquiterpene lactones bioactivity and molec-ular mechanismsrdquo Current Medicinal ChemistrymdashAnti-CancerAgents vol 5 no 3 pp 239ndash249 2005


[60] M S Mueller N Runyambo I Wagner S Borrmann K Dietzand L Heide ldquoRandomized controlled trial of a traditionalpreparation of Artemisia annua L (Annual Wormwood) inthe treatment of malariardquo Transactions of the Royal Society ofTropical Medicine amp Hygiene vol 98 no 5 pp 318ndash321 2004

[61] M Harmsma M Gromme M Ummelen W Dignef KJ Tusenius and F C S Ramaekers ldquoDifferential effects ofViscum album extract IscadorQu on cell cycle progression andapoptosis in cancer cellsrdquo International Journal of Oncology vol25 no 6 pp 1521ndash1529 2004

[62] S Narayan ldquoCurcumin a multi-functional chemopreventiveagent blocks growth of colon cancer cells by targeting 120573-catenin-mediated transactivation and cell-cell adhesion path-waysrdquo Journal of Molecular Histology vol 35 no 3 pp 301ndash3072004

[63] Y Cao Z-D Fu F Wang H-Y Liu and R Han ldquoAnti-angio-genic activity of resveratrol a natural compound from medic-inal plantsrdquo Journal of Asian Natural Products Research vol 7no 3 pp 205ndash213 2005

[64] F Chen T Wang Y-F Wu et al ldquoHonokiol a potent chemo-therapy candidate for human colorectal carcinomardquo WorldJournal of Gastroenterology vol 10 no 23 pp 3459ndash3463 2004

[65] M R Sartippour Z-M ShaoDHeber et al ldquoGreen tea inhibitsvascular endothelial growth factor (VEGF) induction in humanbreast cancer cellsrdquo Journal of Nutrition vol 132 no 8 pp 2307ndash2311 2002

[66] S Yeh H Miyamoto H Shima and C Chang ldquoFrom estrogento androgen receptor a new pathway for sex hormones inprostaterdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 95 no 10 pp 5527ndash5532 1998

[67] P Rizza I Barone D Zito et al ldquoEstrogen receptor beta as anovel target of androgen receptor action in breast cancer celllinesrdquo Breast Cancer Research vol 16 no 1 article R21 2014

[68] I Castellano E Allia V Accortanzo et al ldquoAndrogen receptorexpression is a significant prognostic factor in estrogen receptorpositive breast cancersrdquo Breast Cancer Research and Treatmentvol 124 no 3 pp 607ndash617 2010

[69] W R Polkinghorn J S Parker M X Lee et al ldquoAndrogenreceptor signaling regulates DNA repair in prostate cancersrdquoCancer Discovery vol 3 no 11 pp 1245ndash1253 2013

[70] I G Mills ldquoMaintaining and reprogramming genomic andro-gen receptor activity in prostate cancerrdquoNature Reviews Cancer2014

[71] K Sak ldquoChemotherapy and dietary phytochemical agentsrdquoChemotherapy Research and Practice vol 2012 Article ID282570 11 pages 2012

[72] E-R Hahm J Lee Y Huang and S V Singh ldquoWithaferina suppresses estrogen receptor-120572 expression in human breastcancer cellsrdquo Molecular Carcinogenesis vol 50 no 8 pp 614ndash624 2011

[73] R S Muthyala Y H Ju S Sheng et al ldquoEquol a natural estro-genic metabolite from soy isoflavones convenient preparationand resolution of R- and S-equols and their differing bindingand biological activity through estrogen receptors alpha andbetardquo Bioorganic ampMedicinal Chemistry vol 12 no 6 pp 1559ndash1567 2004

[74] D P Bezerra C Pessoa M O de Moraes N Saker-Neto E RSilveira and L V Costa-Lotufo ldquoOverview of the therapeuticpotential of piplartine (piperlongumine)rdquo European Journal ofPharmaceutical Sciences vol 48 no 3 pp 453ndash463 2013

[75] K V Golovine P B Makhov E Teper et al ldquoPiperlongumineinduces rapid depletion of the androgen receptor in humanprostate cancer cellsrdquoTheProstate vol 73 no 1 pp 23ndash30 2013

[76] I E Wertz and V M Dixit ldquoRegulation of death receptor sig-naling by the ubiquitin systemrdquo Cell Death and Differentiationvol 17 no 1 pp 14ndash24 2010

[77] M E Guicciardi and G J Gores ldquoLife and death by deathreceptorsrdquoTheFASEB Journal vol 23 no 6 pp 1625ndash1637 2009

[78] A Ashkenazi and V M Dixit ldquoDeath receptors signaling andmodulationrdquo Science vol 281 no 5381 pp 1305ndash1308 1998

[79] I Murtaza M Saleem V M Adhami B B Hafeez and HMukhtar ldquoSuppression of cFLIP by lupeol a dietary triterpeneis sufficient to overcome resistance to TRAIL-mediated apop-tosis in chemoresistant human pancreatic cancer cellsrdquo CancerResearch vol 69 no 3 pp 1156ndash1165 2009

[80] K Hata K Ishikawa K Hori and T Konishi ldquoDifferentiation-inducing activity of lupeol a lupane-type triterpene fromChinese dandelion root (Hokouei-kon) on a mouse melanomacell linerdquo Biological and Pharmaceutical Bulletin vol 23 no 8pp 962ndash967 2000

[81] Y Wang B Wang J Cheng et al ldquoFADD-dependent apoptosisinduction in Jurkat leukemia T-cells by the resveratrol ana-logue 345-trihydroxy-trans-stilbenerdquoBiochemical Pharmacol-ogy vol 69 no 2 pp 249ndash254 2005

[82] J A Sprowl K Reed S R Armstrong et al ldquoAlterations intumor necrosis factor signaling pathways are associated withcytotoxicity and resistance to taxanes a study in isogenicresistant tumor cellsrdquo Breast Cancer Research vol 14 no 1article R2 2012

[83] A Shehzad F Wahid and Y S Lee ldquoCurcumin in cancerchemoprevention molecular targets pharmacokinetics bioa-vailability and clinical trialsrdquo Archiv der Pharmazie vol 343no 9 pp 489ndash499 2010

[84] G-W Huang C-X Xie and G-Q Kuang ldquoTreatment of 41patients with advanced stage of nasopharyngeal carcinoma bycombination therapy of radiotherapy and Chinese herbal drugsfor activating blood circulation to remove stasis as hirudordquoChinese Journal of Integrated Traditional and Western Medicinevol 23 no 10 pp 777ndash778 2003

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


36

9

4

10

0

28

13

50

11

9

4

22

4

39

126

9

1

25

8



NNDNBNM

SlowastSlowastNMSNMOthers

All drugs (1981ndash2010)

Figure 1 Sources of anticancer drugs from the 1940s to 2010 lowastNatural product (N) derived from a natural product usually a syntheticderivative (ND) Natural product ldquoBotanicalrdquo (NB) natural product mimic (NM) totally synthetic drug (S) made by total synthesis but thepharmacophore iswas from a natural product (Slowast)

successful due to the initiation of the Cancer ChemotherapyNational Service Center (CCNSC) in 1955 by the NationalCancer Institute (NCI) The mandate of this program was toscreen for antitumor agents on a larger scale by establishinga strict standardized protocol for testing potential anticancercompounds [7]

Since the 1980s research into the anticancer effects ofnatural products has yielded many promising results Forexample resveratrol a polyphenol present in grapes showspotential as both a preventative and an antitumor agent [8]

Similarly piperlongumine extracted from Piper longumselectively induces reactive oxygen species in cancerous cellsleading to apoptotic cell death [9] In the 1980s Bagshawe etal developed a novel use for natural products the antibody-directed enzyme-prodrug therapy (ADEPT) This techniqueused tumor-specific antibodies bound to an enzyme thatwould convert noncytotoxic prodrugs into their cytotoxicforms once in contact with the tumor [10 11] Many natu-ral products were successfully used as prodrugs includingdoxorubicin and Taxol [3] These earlier studies have paved







































































Monoisotopicmass

























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































Monoisotopicmass

























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































Monoisotopicmass

























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































































Monoisotopicmass

























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































Monoisotopicmass

























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































Monoisotopicmass

























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























Monoisotopicmass

























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























Acknowledgments


References




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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