RiewArticle - Hindawi Publishing Corporationdownloads.hindawi.com/journals/ecam/2018/2313021.pdf · in tumor diseases therapy, mainly including resveratrol, polydatin,emodin,andchrysophanicacid(Figure)

Review ArticleAntitumor Research of the Active Ingredients from TraditionalChinese Medical Plant Polygonum Cuspidatum

XinnanWu Qi Li Yu Feng and Qing Ji

Department of Medical Oncology and Cancer Institute of Integrative Medicine Shuguang HospitalShanghai University of Traditional Chinese Medicine Shanghai 201203 China

Correspondence should be addressed to Yu Feng fengyushutcmeducn and Qing Ji ttt99118hotmailcom

Received 13 July 2018 Revised 5 October 2018 Accepted 24 October 2018 Published 21 November 2018

Academic Editor Ho Lin

Copyright copy 2018 Xinnan Wu et al This 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

In recent years the utilization ofChinese nativemedicine and other plant extracts in the treatment of diseases has attracted extensiveattention especially in the area of malignant tumors However lots of herbal remedies active ingredients have not been found orhave been discovered but not effectively developed and applied Therefore screening new Chinese medicine active componentsand determining their antitumor effects have become a new breakthrough in the prevention and treatment of tumor disease Inthe past years a large number of studies have demonstrated that Polygonum cuspidatum and its active components like resveratrolshowed excellent antitumor activities including our own antitumor studies about resveratrol in colorectal cancer The purpose ofthis review is to summarize the research progress of Chinese herb Polygonum cuspidatum and its active components in tumordiseases and provide theoretical basis for further scientific experiments and clinical applications

1 Introduction

With the changes of the diet types and the bad livinghabits malignant tumors have gradually developed into aserious threat to human health and life In the United Statesaccording to the current peak levels [1] from 1991 to 2014overall cancer mortality dropped by 25 however in thepast 2017 years 1688780 new cancer cases and 600920cancer deaths are still expected to occur in USA In 20154292000 new cancer cases and 2814000 cancer deaths havebeen estimated to occur in China [2] according to the datareleased by the National Central Cancer Registry of China

At present the treatment of tumors mainly focuses onsurgery radiation therapy chemotherapy molecular targetedtherapy and immunotherapy But these treatments to someextent easily produce side effects on normal cells organsand other tissues of the human body thus accelerating thedeath process of cancer patients Many natural products andtheir active components have been reported to have potentialantitumor or tumor preventive properties Therefore thefull utilization of some natural products and their activecomponents will provide unique ideas and methods forcancer prevention and treatment Polygonum cuspidatum

Sieb et Zucc a Traditional Chinese medicine (TCM) herbbelongs to polygonaceae It has a long history of being used asa folk medicine in China Japan and Korea Pharmacologicalresearches and clinical studies have indicated that Polygonumcuspidatum extraction and its major compounds possessantitumor [3] anti-inflammatory antivirus antimicrobialneuroprotective and cardioprotective activities [4] Previousresearches completed by our team have also demonstratedthat resveratrol inhibits the proliferation invasion andmetastasis of colorectal cancer cells [5] Therefore we believethat it is necessary to systematically summarize the antitumoreffects of Polygonum cuspidatum and its active componentsand lay a foundation for their clinical development andapplication

2 Antitumor Activities of PolygonumCuspidatum Active Ingredients

Until now many active constituents of Polygonum cuspi-datum have been found such as resveratrol polydatin andanthraquinones (including emodin and its glycoside) It alsocontains flavonoids such as quercetin and (+)-catechin [4] A

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2018 Article ID 2313021 10 pageshttpsdoiorg10115520182313021

2 Evidence-Based Complementary and Alternative Medicine

Resveratrol

OH

OH

HOOH

Antineoplasticingredients

OH OH

O

O

HO

Emodin

OH OH

OO

O

Chrysophanic acid

Polydatin

OH

OH

O

OHOH

OOH

HO（2C

Figure 1 Antitumor components of Polygonum cuspidatum Resveratrol C14H12O3 trans-3t4 and 5-Trihydroxystilbene Poly-datin C20H22O8 341015840-5-Trihydroxystilbene-3-beta-D-glucopyranoside Emodin C15H10O5 and 138-Trihydroxy-6-methylanthraquinoneChrysophanic acid C15H8O6 45-dihydroxy-910-dioxo-9 and 10-dihydroanthracene-2-carboxylic acid

Metabolism

Immunity Invasion

Metastasis

Apoptosis

Gutmicrobiota

Proliferation

Cancerpain Resveratrol

Figure 2 Antitumor effect of resveratrol Resveratrol not only acts on tumor cells themselves but also regulates human immunity andmicroenvironment Moreover it can improve the life quality of cancer patients by improving cancer pain

growing number of researches have shown that the effect ofPolygonum cuspidatum and its active ingredients in cancertreatment is remarkable Here we will review the researchprogress of active components of Polygonum cuspidatumin tumor diseases therapy mainly including resveratrolpolydatin emodin and chrysophanic acid (Figure 1)

21 Antitumor Activity of Resveratrol Resveratrol wasoriginally extracted from the roots of Polygonumcuspidatum which is also found in red wine grapesand peanuts [6] Many health benefits have been linkedto it including antitumor [7] anti-inflammation [6]antioxidation [8] immunoregulation [9] and even gutmicrobiota-regulation [10] Currently resveratrol hasattracted attention of researchers for its antitumor effect ina variety of human cancer cell lines through the regulationof various molecular targets [11] Its antitumor roles

cover almost all aspects of cancer including tumor cellproliferation invasion metastasis apoptosis [7] immunity[12] metabolism [13] and intestinal flora [14] (Figure 2)

211 Resveratrol and Tumor Proliferation Invasion Metas-tasis and Apoptosis In the past few years resveratrol hasbeen found to play important roles in tumor progressionincluding proliferation invasion metastasis and apoptosis(Figure 3) Resveratrol is a potent natural activator of sirtuin-1 (SIRT1) a nuclear substance associated with the histonedeacetylases class III [15] Moreover resveratrol can inhibitepithelial mesenchymal transition (EMT) associated cancercell invasion and migration through the inhibition of the PI-3KAktNF-B TGF-1205731 and hedgehog signaling pathway[16ndash18] As our previous experiments in vitro have shownTGF-1205731-induced EMT promoted the invasion and metastasisof colorectal cancer but resveratrol could inhibit the invasive

Evidence-Based Complementary and Alternative Medicine 3

InvasionMetastasis

mRNASTAT-3

cytotoxicity

Cell cyclegene products

Proliferation Apoptosis

Anti-apoptotic gene products

FAK-ICYTD

OH

HOOH

RES

TGF-HedgehogPI-3KAktNF-ҡB

Figure 3 Effect of resveratrol on the proliferation invasionmetastasis and apoptosis of tumor cells Resveratrol can restrain the proliferationof multiple cancer cells through modulation of cell-cycle regulatory gene products and induce the cancer cells apoptosis by inhibition ofantiapoptotic gene products Resveratrol can inhibit EMT associated cancer cell invasion and migration through the inhibition of the PI-3KAktNF-B TGF-1205731 and hedgehog signaling pathway Resveratrol displayed a dose-dependent and time-dependent cytotoxicity onlung cancer cells A549 through inhibiting the mRNA and protein expression of STAT-3 Resveratrol can enhance the anti-invasion andantimetastasis effect of FAK-I and CYTD when they were used in combination

and migratory ability of LoVo cells in a concentration-dependent manner through regulating TGF-1205731Smads sig-naling pathway mediated SnailE-cadherin expression [19]

Nuclear factor-kappa B (NF-B) is a critical elementwhich regulates kinds of pathophysiological processesincluding proliferation invasion metastasis differentiationand apoptosis of different tumor cells [20] Resveratrol is aspecific inhibitor of NF-B in different tumor cells [21] itcan downregulate the nuclear localization of NF-B phos-phorylation and its acetylation which cause attenuation ofNF-B-regulated gene products (MMP-9 CXCR4) involvedin tumor-invasion and metastasis [22] Resveratrol can alsodownregulate NF-B signaling pathway by inhibiting activa-tion of IB120572 kinase and IB120572 phosphorylation in colorectalcancer cells Additionally the regulation of intercellularjunctions and EMT is one of the principle mechanisms ofresveratrol on the inhibition of tumor growth and invasion[23] Resveratrol can restrain the proliferation of multiplecancer cells through modulation of cell-cycle regulatorygene products and induce the cancer cells apoptosis byupregulation of p53 and inhibition of antiapoptotic geneproducts [24]

Resveratrol can inhibit the phosphorylation of focal adhe-sion kinase (FAK) in various cancer cell lines [25] Moreoverresveratrol displayed a dose-dependent and time-dependentcytotoxicity on lung cancer cells A549 through inhibitingthe mRNA and protein expression of STAT-3 while over-expression of STAT-3 completely or partially blocked the

effects of resveratrol on A549 cells [26] The recombinationand reconfiguration of cytoskeleton are very important forthe invasion and metastasis of cancer cells FAK-I (FAK-inhibitor) and CYTD (cytochalasin D) can inhibit the inva-sion andmetastasis effect of cancer cells while resveratrol canenhance the anti-invasion and antimetastasis effect of FAK-Iand CYTD when they were used in combination [27]

212 Resveratrol and Immunity It is well-understood thatradiation therapy is one of the most important treatmentmethods for cancers [28] However radiation may damagethe DNA cells and organs and cause side effects associ-atedwith antiproliferation proinflammation profibrosis andeven patientsrsquo immune system imbalance [29] It has beenreported that radiation-induced production and inflamma-tion can be preventedwith flavonoids including phenols suchas resveratrol

Spleen is the largest immune organ in mammals Themaintenance of splenic lymphocytes plays an important rolein the normal immune function Studies have shown thatresveratrol can protect the immune function of spleen whichis manifested in the fact that it can significantly reverserestraint-induced declines of spleen index and splenocytenumber In addition resveratrol plays an important role inprotecting spleen cell mitochondria from oxidative stress[30]

It is well-known that T lymphocytes play an importantrole in cellular immunity such as killing target cells reacting


to specific antigens and producing cytokines In mature Tlymphocytes CD4+ and CD8+ T cells are two importantsubsets of immune regulation [30] CD4+ and CD8+ T cellsare essential for OX 40 agonist mediated tumor immune sys-tem [31] The data has shown that resveratrol could increasethe proportion and quantity of CD4+ T cells [30] Howeverduring the treatment of OX 40 agonist supplementationof resveratrol could not maintain the antitumor immunefunction [28] The effect of resveratrol on tumor growth andradiation-induced immune dysfunction is not significantwhich may be affected by the bioavailability of resveratrolsince more than 50 of resveratrol is bioavailable in rodentsand humans shortly after intake [28]

It is believed that the bodyrsquos immunity system includingmacrophages neutrophils and natural killer cells decreaseswith age [32] This adaptive change in immune function canlead to a state of immune deficiency and affect tumor immuneresponses Therefore restoring or maintaining antitumorimmunity in elderly cancer patients can improve the efficacyof immunotherapy [30] Calorie restriction is the mostreliable way tomaintain immune function in elderly patientsNevertheless because of the difficulty in maintaining caloriefor a long time it is necessary to consider the immuneprotection of tumors maintained by calorie mimics such asresveratrol during aging andmore experiments are needed tofully determine whether resveratrol can maintain immunityduring aging to prevent tumorigenesis or inhibit cancer cells[28]

213 Resveratrol and Gut Microbiota Studies have shownthat gut microflora has an impact on human health anddisease which involves the potential of drug targetingand metabolism TCM may restore homeostasis in humansby regulating gut microbes and restore metabolicimmunehomeostasis by modulating genes within the host [33] Thiswill be of great help to the prevention and treatment ofvarious types of bowel cancers [14]

Several mechanisms of resveratrol have been proposedincluding modulating the gut microbiotacan gut integrityand barrier function [10] The effect of resveratrol on theintestinal flora is primarily that it preferentially slows downthe growth of certain microbes leading to a more favorablemicrobial distribution [10] In addition resveratrol metabo-lites produced by gut microflora have distinct biologicaleffects which may have guiding significance for the studyof digestive tract tumors [10] The physiological effects ofresveratrol are in striking contrast to its low bioavailabilitywhich is a major problem for the development of the kind ofcompounds into therapeutic agents However the evidencesupports the opinion that phenolic phytochemicals with lowbioavailability are possibly playing a role through remodelingthe gut microbiota [34] All above results suggested thatresveratrol can significantly modulate the gut microbiota toimprove intestinal microenvironment and further preventthe occurrence and development of tumors [35]

214 Resveratrol and Metabolism Like normal cellsmetabolism is necessary for cancer cells to generateenergy for promoting cell proliferation [36] Increased

glucose uptake and lactate production are marks of cancermetabolism [37] The effect mechanism of resveratrolon cancer metabolism has been found in several aspects(Figure 4) Firstly the regulation of glucose transporter(GLUT) and glycolytic enzyme activity by AKT is one ofthe mechanisms of metabolic phenotype in cancer cells[38] and resveratrol can regulate the glucose metabolism byblocking the transport of GLUT1 to the plasma membranevia inhibiting the activation of AKT [39] Secondly theinhibition of enzyme 6-phosphofructo-1-kinase (PFK)could result in the death of human breast cancer cell linesand tissues [40] while resveratrol could directly inhibitthe activity of purified PFK thus providing a new targetfor the antibreast tumor [41] Thirdly the pyruvate kinaseM2 (PKM2) is the key to tumor metabolism and growth[42] and the resveratrol can inhibit cancer metabolism byaffecting the state of PKM2 [43] Furthermore mitochondrialdysfunction associated with tumors leads to a significantincrease in reactive oxygen species (Ros) production [44]but resveratrol can inhibit reactive oxygen species and reduceoxidative stress through the degradation of Keap 1 proteinwhich is a repressor of Nrf2 [45]

215 Resveratrol and Inflammation Inflammation has beenconsidered to be a ldquohallmark of cancerrdquo [46] Epidemiologicaland clinical studies have made it clear that about 25 of solidtumors are associated with chronic inflammation [47] Incancer inflammation is a continuous process and persistentchronic inflammatory response will promote tumor prolif-eration angiogenesis invasion and metastasis In additioninflammation EMT endoplasmic reticulum (ER) stress andmetabolism often interact with each other affecting theoccurrence and development of tumor [48]

Several reports have shown the important regulatoryeffect of resveratrol on inflammation throughdifferent targetsand various signaling pathways (Figure 5) Suppressor ofcytokine signaling 1 (SOCS1) is typically perceived as a tumorsuppressor and silencing of the SOCS1 gene by hyperme-thylation in its promoter region is frequent in many typesof cancer However the role of SOCS1 in colorectal cancerhas been poorly investigated [49] Resveratrol exerts anti-inflammatory effects through the upregulation of SOCS1which is a potential target of miR-155 At the same timeresveratrol inhibits STAT activation and enhances SOCS1expression by attenuating the production of miR-155 Thesefindings suggest that resveratrol may be developed as auseful agent for the treatment of inflammatory diseasesIn addition resveratrol inhibits the production of proin-flammatory cytokines and inhibits the activation of the p38mitogen-activated protein kinase (MAPK) and STAT1STAT3signaling pathways by upregulating SOCS1 expression inresponse to LPS stimulation [50]

Estrogen receptor-120572 (ER120572) is an important transcriptionfactor that modulates cell growth in various tissues [51]which is closely associated with the development of multiplecancers especially endometrial carcinoma and breast cancerNwachukwu et al have found that the anti-inflammatoryresponse of resveratrol was related to the binding of ER120572which changes the shape of the receptor through the


Immunity

Spleen

CD4+ T cells

Gutmicrobiota

Function

Integrity

Microbiotica

Ros Oxidative stress

Metabolism

Glucose

PKM2

PFK

OH

HOOH

RES

Figure 4 Effect of resveratrol on immunity gut microbiota andmetabolism Resveratrol could protect spleen immune function and reversethe decrease of spleen index and spleen cell number Resveratrol could increase the proportion and quantity of CD4+ T cells It improvesthe intestinal environment including modulating the gut microbiotacan gut integrity and barrier function The anticancer mechanism ofresveratrol is related to the regulation of glucosemetabolism It inhibits themetabolism of tumor by affecting the state of PKM2 and decreasesintracellular reactive oxygen species production and oxidative stress through mechanisms involving degradation of Keap 1 protein which isa repressor of Nrf2

Inflammation

SOCS1

Pro-inflammatory cytokines

MAPK STAT1STAT3

miR-155

STAT SOCS1

OH

HOOH

RES

ER

Figure 5 Resveratrol and inflammation Resveratrol inhibits STAT activation and enhances SOCS1 expression by attenuating the productionof miR-155 Resveratrol inhibits the production of proinflammatory cytokines and inhibits the activation of the p38MAPK and STAT1STAT3signaling pathways by upregulating SOCS1 expression The anti-inflammatory response of resveratrol was related to the binding of ER120572

coregulator molecules to regulate transcription [52] Resver-atrol is a transduction selective ER120572 ligand which adjusts theinflammatory response without stimulating proliferation bydynamically binding with the receptor and induces an alteredactivation function 2 coactivator-binding site In addition italso regulates the recruitment of a cast of coregulators at theIL-6 locus [6]

216 Resveratrol and Cancer Pain Cancer pain is one of themost common clinical symptoms associated with malignantcancers [53] Nowadays opioids are used to treat moderate tosevere pain Among them morphine is an effective analgesic

for treatingmoderate to severe pain [54] However long-termmorphine administration induces tolerance [54] and robustactivation of spinal microglia and even resulted in a markedreduction in the analgesic properties [55] which hampers itsclinical use Therefore it is urgent to treat cancer pain safelyand effectively

Resveratrol possesses potentially analgesic effects [56]and it has no known toxic side effects Therefore resvera-trol may constitute an effective safe and convenient treat-ment option for cancer patients experiencing severe pain(Figure 6) Long-termmorphine infusion inducedN-methyl-D-aspartate receptor (NMDAR) NR1 and NR2B subunit


Neuro-Inflammation

Restrain

NR1NR2B

Spinal glial activation

CX3CR1

Cancer pain

OH

HO

OH

RES

Figure 6 Resveratrol and cancer pain Resveratrol can mitigate morphine tolerance through restraining neuroinflammation anddownregulating NMDARNR1 and NR2B subunit expressionThe suppression of spinal glial activation and CX3CR1 upregulation is anothermechanism of the analgesic effects of resveratrol

upregulation in synaptosomal membrane of morphine-tolerant rat lumbar spinal cords which was suppressed bythe resveratrol treatment [54] Resveratrol can mitigate mor-phine tolerance through restraining neuroinflammation anddownregulating NR1 and NR2B expression [54] Someonealso found out reduction of postsynaptic membrane PSD-95(postsynaptic density-95) NMDAR expression by resveratroltreatment may be responsible for attenuating glial activationin morphine-tolerant rat spinal cords [54]

Researchers have unearthed that resveratrol can signifi-cantly inhibit the morphine-inducedmicroglia cell activationand migration The suppression of spinal glial activationand CX3C chemokine receptor 1 (CX3CR1) upregulation isanother mechanism of the analgesic effects of resveratrol[55] At present resveratrol could delay and attenuate cancer-induced pain facilitation through intrathecal administrationand resveratrol could also attenuate cancer pain inducedCX3CR1 upregulation and glial activation in the spine [55]

22 Antitumor Activity of Polydatin Polydatin is a stilbenoidcompound isolated from the root of Polygonum cuspidatum[57] as resveratrol derivative with a glucopyranoside ringsubstitution of the hydroxyl group in position three hashigher stability has water solubility and is more resistant toenzymatic oxidation and even has a strong cytotoxicity andis able to enter cells via glucose transporters [58ndash60] It isprecisely because of these characteristics that polydatin has

greater bioavailability than resveratrol and thus has a betterpreventive and therapeutic effect on cancer (Figure 7)

As a rule apoptosis is regulated by proapoptotic andantiapoptotic proteins of the Bcl-2 family and is executedthrough caspases or cysteine-aspartic proteases [57] Theresults of the present study showed that polydatin inducesapoptosis effectively with an increase in Bax expressionand a decrease in Bcl-2 expression in lung cancer cellsproviding a theoretical basis for the prevention and treatmentof lung cancer by polydatin In other studies polydatin has asignificant time- and dose-dependent inhibitory effect on theproliferation inhibition and apoptosis induction of HCC cells[61] In addition polydatin can induce apoptosis of humanosteosarcoma cells by upregulation of the ratio of BaxBcl-2 Reactive oxygen species are mediators of intracellularsignaling cascades that can induce apoptosis associated withmitochondria Excessive production of Ros triggers oxidativestress loss of cell function and even apoptosis [62] At thesame time polydatin can promote the apoptosis throughinducing the production of Ros which triggers endoplasmicreticulum (ER) stress and mitochondrial apoptotic pathwaysin human nasopharyngeal carcinoma CNE cells [60]

In mammalian the core cell-cycle mechanism compris-ing cyclin and cyclin-dependent kinase complex is the maincause of cell proliferation [63] D-type cyclins are typicaltargets and crucial signaling molecules for cancer treatment[64] Among them cyclin D1 is an importantly regulatoryfactor in cell-cycle progression and it plays a transcriptional


Creb

BaxBcl-2

BaxBcl-2

ROS

Polydatin

Breast cancer cells

Lung cancercells

CNE cells

AMC-HN-8Hep-2 cells

Caco-2cells

Osteosarcomacells

OH

OH

O

OH

OHO

OH

HOHC

Figure 7 Cell selectivity of polydatin Polydatin induces apoptosis effectively with an increase in Bax expression and a decrease in Bcl-2expression in lung cancer cells Polydatin has a significant time- and dose-dependent inhibitory effect on the proliferation inhibition andapoptosis induction of HCC cells Polydatin can induce apoptosis of human osteosarcoma cells by upregulation of the ratio of BaxBcl-2Polydatin can induce the production of ROS which triggers ER stress and mitochondrial apoptotic pathways in CNE cells It has a strongcytotoxicity to the growing Caco-2 cells Polydatin can inhibit the activation of Creb and the aim of inhibiting the proliferation of breastcancer cells

coregulator role [65] Cyclin D1 is necessary for tumormaintenance [66] and cell-cycle regulation is an effectivestrategy for inhibiting tumor growth [67] Polydatin shows itsantiproliferation effect by inhibiting the expression of cyclinD1 and cyclin B1 resulting in cell-cycle arrest in S-phase [66]

CAMP response element-binding proteins (Creb) are acharacteristic transcription element of the leucine zipperfamily [68] Creb is a significant factor affecting differentsolid tumors genesis and metastasis For example in breastcancer patients with a poor prognosis metastatic disease andnodal involvement [69] the level of Creb 1 was significantlyupregulated A report has demonstrated that polydatin cansignificantly reduce the phosphorylation level of Creb in adose-dependent manner leading to the inactivation of Crebfollowed by the proliferation inhibition of breast cancer cells[70]

In previous studies polydatin lonely or in combinationwith resveratrol was found to inhibit growth and differ-entiation of Caco-2 cells [59] Compared with resveratrolpolydatin has better cell selectivity It has a strong cytotoxicityto the growing Caco-2 cells and its toxicity is about 3 timeslower in the differentiated Caco-2 cell [59] In addition theselectivity of polydatin is also reflected in human nasopha-ryngeal carcinoma CNE cells For instance it can induce theproduction of reactive oxygen species to trigger ER stressand mitochondrial apoptotic pathways [60] All these resultssuggest that polydatin plays a cytotoxic role through themechanisms that are different from resveratrol

23 Antitumor Studies of other Active Components from Poly-gonum Cuspidatum Some other active components fromPolygonum cuspidatum have been found to have antitumoractivities such as emodin and chrysophanic acid (Figure 8)Emodin as one of the main active components of Polygonumcuspidatum has anti-inflammatory and antioxidative [71]antimicrobial [72] and antitumor effects [73] as resveratrolEmodin has been shown to have strong antitumor activity

HO

O

O

HO

OH HO OH

OHOO

O

Oral cancer cells

MCF-7MDA-MB-231SW620 cells

EGFRmTORSp1caspase-dependent

Emodin Chrysophanic acid

Figure 8 Antitumor effects of emodin and chrysophanic acidEmodin can inhibit the growth of oral cancer cells by reducingSp1 and inducing caspase-dependent apoptosis Chrysophanic acidhas anticancer activity through its effect on EGFRmTOR mediatedsignaling transduction pathway

in oral cancer cells It can inhibit the growth of oral cancercells by reducing specificity protein 1 (Sp1) and inducecaspase-dependent apoptosis suggesting that emodinmay bea potential bioactive substance to induce apoptosis [74]

Chrysophanic acid another active component of Poly-gonum cuspidatum has antiproliferative effect on humanbreast cancer cells MCF-7 and MDA-MB-231 as well as thehuman colon cancer cells SW620 [75 76] Chrysophanicacid also inhibits the activation of EGF-induced epidermalgrowth factor receptor (EGFR) and the downstream signalingmolecules including AKT mTOR and ribosomal protein S6kinase These findings indicate that chrysophanic acid hasanticancer activity through its effect on EGFRmTOR medi-ated signaling transduction pathway In addition combinedapplication of chrysophanol acid and mTOR inhibitors mayenhance the antiproliferation effect [77]


3 Problems and Prospects

In last several years the good curative effect of TCM intreating some difficult diseases has been widely acknowl-edged Polygonum cuspidatum as a kind of herbs is richin resources and widely used in clinical practice of TCMtreatment Modern studies have shown that Polygonumcuspidatum has a remarkable curative effect in the preventionand treatment of tumor diseases

However there are still many problems in the develop-ment and utilization of Polygonum cuspidatum or even otherChinese herbal medicines Firstly the current technology isinsufficient to completely explain the complex compositionof herbal medicines There are hundreds of active ingredientsin natural plant medicines however due to the limitationsof current science and technology only a part of the activeingredients can be extracted and characterized The limitedefficacy and scope of application of these extracts may berelated to the undiscovered active ingredients in the sameplant Secondly as a worldwide disease the pathogenesis oftumors is not well-understood Therefore in the targetedtherapy the effects of the active ingredients from TCM arenot fully exerted For example if the concentration of someenzymes in the tumormicroenvironment can be determinedthe concentration of enzymes would be selectively increasedto enhance the bioavailability of herbs and their activecomponents Thirdly at present the screening techniquesare faultiness on the effective components of the TCM Atthe same time it is well-known that the medicinal effectof the TCM has a great relationship with the dosage Weshould constantly develop new technology strengthen theidentification of new active components and clarify themechanism of TCM and its active components in order toimprove the bioavailability of drugs In addition the signalpathway relationship between components of TCM is notsupported by enough data Different modifications may leadto different target pathways and changes in cellular activityTherefore it is necessary to further study the relationshipbetween herbs components and signal transduction pathwayLast but not least a lot ofmalignant cancer patients have shortsurvival time and earlier intervention in tumor treatmentwhich caused great disturbance and uncertainty for theclinical research of TCM and its effective components

In future research we should intensify the research on theclinical trials to eliminate the interference factors on curativeeffect observation and improve the overall therapeutic effec-tiveness of cancer patients

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

This study is supported by theNationalNatural Science Foun-dation of China (81520108031 81573749 81573478 81673783and 81603457) and Program for Outstanding Medical Aca-demic Leader and Shanghai Academic Research Leader(16XD1403600)

References

[1] R L Siegel K D Miller and A Jemal ldquoCancer statistics 2017rdquoCA A Cancer Journal for Clinicians vol 67 no 1 pp 7ndash30 2017

[2] WChen R Zheng PD Baade et al ldquoCancer statistics inChina2015rdquoCA A Cancer Journal for Clinicians vol 66 no 2 pp 115ndash132 2016

[3] L Zhang Y Li Z Gu et al ldquoResveratrol inhibits enterovirus71 replication and pro-inflammatory cytokine secretion inrhabdosarcoma cells through blocking IKKsNF-120581B signalingpathwayrdquo PLoS ONE vol 10 no 2 Article ID e0116879 2015

[4] H Zhang C Li S-T Kwok Q-W Zhang and S-W ChanldquoA review of the pharmacological effects of the dried rootof Polygonum cuspidatum (Hu Zhang) and its constituentsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 208349 13 pages 2013

[5] Q Ji X Liu X Fu et al ldquoResveratrol inhibits invasion andmetastasis of colorectal cancer cells via MALAT1 mediatedWnt120573-catenin signal pathwayrdquo PLoS ONE vol 8 no 11 ArticleID e78700 2013

[6] J C Nwachukwu S Srinivasan N E Bruno A A Parent T SHughes and J A Pollock ldquoResveratrol modulates the inflam-matory response via an estrogen receptor-signal integrationnetworkrdquo Elife vol 3 2014

[7] GHan J Xia J Gao Y InagakiW Tang andNKokudo ldquoAnti-tumor effects and cellular mechanisms of resveratrolrdquo Drugdiscoveries amp therapeutics vol 9 no 1 pp 1ndash12 2015

[8] S I Jeong J A Shin S Cho et al ldquoResveratrol attenuatesperipheral and brain inflammation and reduces ischemic braininjury in aged female micerdquo Neurobiology of Aging vol 44 pp74ndash84 2016

[9] A Kowalska A K Siwicki and R K Kowalski ldquoDietaryresveratrol improves immunity but reduces reproduction ofbroodstock medaka Oryzias latipes (Temminck amp Schlegel)rdquoFish Physiology and Biochemistry vol 43 no 1 pp 27ndash37 2017

[10] J K Bird D Raederstorff P Weber and R E SteinertldquoCardiovascular and antiobesity effects of resveratrol mediatedthrough the gut microbiotardquo Advances in Nutrition vol 8 no6 pp 839ndash849 2017

[11] J Ko G Sethi J Um et al ldquoThe role of resveratrol in cancertherapyrdquo International Journal of Molecular Sciences vol 18 no12 p 2589 2017

[12] L Chen S Yang W Liao and Y Xiong ldquoModification of anti-tumor immunity and tumor microenvironment by resveratrolin mouse renal tumor modelrdquoCell Biochemistry and Biophysicsvol 72 no 2 pp 617ndash625 2015

[13] M Pieszka P Szczurek K Ropka-Molik M Oczkowicz andM Pieszka ldquoThe role of resveratrol in the regulation of cellmetabolism - A reviewrdquo Postepy Higieny i Medycyny Doswiad-czalnej vol 70 pp 117ndash123 2016

[14] F Chen Q Wen J Jiang et al ldquoCould the gut microbiotareconcile the oral bioavailability conundrum of traditionalherbsrdquo Journal of Ethnopharmacology vol 179 pp 253ndash2642016

[15] R L Moore Y Dai and D V Faller ldquoSirtuin 1 (SIRT1)and steroid hormone receptor activity in cancerrdquo Journal ofEndocrinology vol 213 no 1 pp 37ndash48 2012

[16] W Li J Ma Q Ma et al ldquoResveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via sup-pression of the PI-3KAktNF-120581B pathwayrdquo Current MedicinalChemistry vol 20 no 33 pp 4185ndash4194 2013


[17] HWangH Zhang L Tang et al ldquoResveratrol inhibits TGF-1205731-induced epithelial-to-mesenchymal transition and suppresseslung cancer invasion and metastasisrdquo Toxicology vol 303 pp139ndash146 2013

[18] J Li T Chong Z Wang et al ldquoA novel anti-cancer effect ofresveratrol Reversal of epithelial- mesenchymal transition inprostate cancer cellsrdquo Molecular Medicine Reports vol 10 no4 pp 1717ndash1724 2014

[19] Q Ji X Liu Z F Han et al ldquoResveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-1205731Smads signaling pathwaymediated SnailE-cadherin expres-sionrdquo BMC Cancer vol 15 article 97 2015

[20] J S Chung S Lee and Y D Yoo ldquoConstitutive NF-120581Bactivation and tumor-growth promotion by Romo1-mediatedreactive oxygen species productionrdquo Biochemical and Biophys-ical Research Communications vol 450 no 4 pp 1656ndash16612014

[21] D A Benitez M A Hermoso E Pozo-Guisado P MFernandez-Salguero and E A Castellon ldquoRegulation of cellsurvival by resveratrol involves inhibition of NF120581B-regulatedgene expression in prostate cancer cellsrdquo e Prostate vol 69no 10 pp 1045ndash1054 2009

[22] C Buhrmann P Shayan B Popper A Goel and M ShakibaeildquoSirt1 is required for resveratrol-mediated chemopreventiveeffects in colorectal cancer cellsrdquo Nutrients vol 8 no 3 2016

[23] C Buhrmann P Shayan P Kraehe B Popper A Goel andM Shakibaei ldquoResveratrol induces chemosensitization to 5-fluorouracil through up-regulation of intercellular junctionsepithelial-to-mesenchymal transition and apoptosis in colorec-tal cancerrdquo Biochemical Pharmacology vol 98 no 1 pp 51ndash582015

[24] V P Androutsopoulos K C Ruparelia A Papakyriakou HFilippakis A M Tsatsakis and D A Spandidos ldquoAnticancereffects of the metabolic products of the resveratrol analogueDMU-212 Structural requirements for potencyrdquoEuropean Jour-nal of Medicinal Chemistry vol 46 no 6 pp 2586ndash2595 2011

[25] J Vanamala S Radhakrishnan L Reddivari V B Bhat andA Ptitsyn ldquoResveratrol suppresses human colon cancer cellproliferation and induces apoptosis via targeting the pentosephosphate and the talin-FAK signaling pathwaysmdasha proteomicapproachrdquo Proteome Science vol 9 article 49 2011

[26] X Li D Wang Q C Zhao T Shi and J Chen ldquoResveratrolinhibited nonndashsmall cell lung cancer through inhibiting STAT-3 signalingrdquo e American Journal of the Medical Sciences vol352 no 5 pp 524ndash530 2016

[27] J B Stokes S J Adair J K Slack-Davis et al ldquoInhibition offocal adhesion kinase by PF-562271 inhibits the growth andmetastasis of pancreatic cancer concomitant with altering thetumor microenvironmentrdquoMolecular Cancer erapeutics vol10 no 11 pp 2135ndash2145 2011

[28] M Farazi J Nguyen J Goldufsky et al ldquoCaloric restrictionmaintains OX40 agonist-mediated tumor immunity and CD4T cell priming during agingrdquoCancer Immunology Immunother-apy vol 63 no 6 pp 615ndash626 2014

[29] K-O Kim H Park M Chun and H-S Kim ldquoImmunomod-ulatory effects of high-protein diet with resveratrol supplemen-tation on radiation-induced acute-phase inflammation in ratsrdquoJournal of Medicinal Food vol 17 no 9 pp 963ndash971 2014

[30] W-J Duan F-L Liu R-R He et al ldquoAutophagy is involved inthe effects of resveratrol on prevention of splenocyte apoptosiscaused by oxidative stress in restrained micerdquoMolecular Nutri-tion amp Food Research vol 57 no 7 pp 1145ndash1157 2013

[31] J Kjaergaard J Tanaka J A Kim K Rothchild A Weinbergand S Shu ldquoTherapeutic efficacy of OX-40 receptor antibodydepends on tumor immunogenicity and anatomic site of tumorgrowthrdquo Cancer Research vol 60 no 19 pp 5514ndash5521 2000

[32] E J Kovacs J L Palmer C F Fortin T Fulop Jr D RGoldstein and P-J Linton ldquoAging and innate immunity inthe mouse impact of intrinsic and extrinsic factorsrdquo Trends inImmunology vol 30 no 7 pp 319ndash324 2009

[33] L Zhao J K Nicholson A Lu et al ldquoTargeting the humangenome-microbiome axis for drug discovery Inspirations fromglobal systems biology and traditional Chinese medicinerdquoJournal of Proteome Research vol 11 no 7 pp 3509ndash3519 2012

[34] N-R Shin J-C Lee H-Y Lee et al ldquoAn increase in theAkkermansia spp population induced by metformin treatmentimproves glucose homeostasis in diet-induced obesemicerdquoGutvol 63 no 5 pp 727ndash735 2014

[35] M-L Chen L Yi Y Zhang et al ldquoResveratrol attenuatestrimethylamine-N-oxide (TMAO)-induced atherosclerosis byregulating TMAO synthesis and bile acid metabolism viaremodeling of the gut microbiotardquomBio vol 7 no 2 2016

[36] P S Ward and C B Thompson ldquoMetabolic reprogramming acancer hallmark even warburg did not anticipaterdquo Cancer Cellvol 21 no 3 pp 297ndash308 2012

[37] Y Kato T Maeda A Suzuki and Y Baba ldquoCancermetabolismNew insights into classic characteristicsrdquo Japanese Dental Sci-ence Review vol 54 no 1 pp 8ndash21 2018

[38] R A Cairns I S Harris and T W Mak ldquoRegulation of cancercell metabolismrdquo Nature Reviews Cancer vol 11 no 2 pp 85ndash95 2011

[39] H Gwak G Haegeman B K Tsang and Y S Song ldquoCancer-specific interruption of glucose metabolism by resveratrol ismediated through inhibition of AktGLUT1 axis in ovariancancer cellsrdquoMolecular Carcinogenesis vol 54 no 12 pp 1529ndash1540 2015

[40] R G Coelho I D C Calaca D D M Celestrini A HCorreia M A S M Costa and M Sola-Penna ldquoClotrimazoledisrupts glycolysis in human breast cancer without affectingnon-tumoral tissuesrdquo Molecular Genetics and Metabolism vol103 no 4 pp 394ndash398 2011

[41] L S Gomez P Zancan M C Marcondes et al ldquoResveratroldecreases breast cancer cell viability and glucosemetabolism byinhibiting 6-phosphofructo-1-kinaserdquo Biochimie vol 95 no 6pp 1336ndash1343 2013

[42] C Beinat I S Alam M L James A Srinivasan and S SGambhir ldquoDevelopment of [(18)F]DASA-23 for imaging tumorglycolysis throughnoninvasivemeasurement of pyruvate kinaseM2rdquoMolecular Imaging and Biology vol 19 no 5 pp 665ndash6722017

[43] M A Iqbal and R N K Bamezai ldquoResveratrol inhibits cancercell metabolism by down regulating pyruvate kinase M2 viainhibition of Mammalian target of Rapamycinrdquo PLoS ONE vol7 no 5 2012

[44] R Benfeitas M Uhlen J Nielsen and A Mardinoglu ldquoNewchallenges to study heterogeneity in cancer redox metabolismrdquoFrontiers in Cell and Developmental Biology vol 5 2017

[45] Y Liu F Chan and H Sun ldquoResveratrol protects humankeratinocytes HaCaT cells from UVA-induced oxidative stressdamage by downregulating Keap1 expressionrdquo European Jour-nal of Pharmacology vol 650 no 1 pp 130ndash137 2011

[46] DHanahan andR AWeinberg ldquoHallmarks of cancer the nextgenerationrdquo Cell vol 144 no 5 pp 646ndash674 2011


[47] L M Coussens and Z Werb ldquoInflammation and cancerrdquoNature vol 420 no 6917 pp 860ndash867 2002

[48] J Liu P C Lin and B P Zhou ldquoInflammation fuels tumorprogress and metastasisrdquo Current Pharmaceutical Design vol21 no 21 pp 3032ndash3040 2015

[49] C Beaurivage A ChampagneW S TobelaimV PomerleauAMenendez and C Saucier ldquoSOCS1 in cancer An oncogene anda tumor suppressorrdquo Cytokine vol 82 pp 87ndash94 2016

[50] P T Pfluger D Herranz S Velasco-Miguel M Serrano andM H Tschop ldquoSirt1 protects against high-fat diet-inducedmetabolic damagerdquo Proceedings of the National Acadamy ofSciences of the United States of America vol 105 no 28 pp9793ndash9798 2008

[51] W Zhou and J M Slingerland ldquoLinks between oestrogenreceptor activation and proteolysis relevance to hormone-regulated cancer therapyrdquo Nature Reviews Cancer vol 14 no1 pp 26ndash38 2014

[52] J C Nwachukwu M R Southern J R Kiefer et alldquoImproved crystallographic structures using extensive combi-natorial refinementrdquo Structure vol 21 no 11 pp 1923ndash19302013

[53] P Mantyh ldquoBone cancer pain causes consequences andtherapeutic opportunitiesrdquo PAIN vol 154 supplement 1 ppS54ndashS62 2013

[54] R-Y Tsai K-Y Chou C-H Shen et al ldquoResveratrol regu-lates N-methyl-D-aspartate receptor expression and suppressesneuroinflammation in morphine-tolerant ratsrdquo Anesthesia ampAnalgesia vol 115 no 4 pp 944ndash952 2012

[55] W Cheng Y Zhao H Liu et al ldquoResveratrol attenuates bonecancer pain through the inhibition of spinal glial activation andCX3CR1 upregulationrdquo Fundamental amp Clinical Pharmacologyvol 28 no 6 pp 661ndash670 2014

[56] G Wang Z Hu X Song et al ldquoAnalgesic and anti-inflammatory activities of resveratrol through classic models inmice and ratsrdquo Evidence-Based Complementary and AlternativeMedicine vol 2017 Article ID 5197567 9 pages 2017

[57] Y Zhang Z Zhuang Q Meng Y Jiao J Xu and S FanldquoPolydatin inhibits growth of lung cancer cells by inducingapoptosis and causing cell cycle arrestrdquo Oncology Letters vol7 no 1 pp 295ndash301 2014

[58] M N Krasnow and T M Murphy ldquoPolyphenol glucosylatingactivity in cell suspensions of grape (Vitis vinifera)rdquo Journal ofAgricultural and Food Chemistry vol 52 no 11 pp 3467ndash34722004

[59] S De Maria I Scognamiglio A Lombardi et al ldquoPolydatina natural precursor of resveratrol induces cell cycle arrestand differentiation of human colorectal Caco-2 cellrdquo Journal ofTranslational Medicine vol 11 no 1 article no 264 2013

[60] H Liu S Zhao Y Zhang et al ldquoReactive oxygen species-mediated endoplasmic reticulum stress andmitochondrial dys-function contribute to polydatin-induced apoptosis in humannasopharyngeal carcinoma CNE cellsrdquo Journal of Cellular Bio-chemistry vol 112 no 12 pp 3695ndash3703 2011

[61] Y Jiao Y Wu and D Du ldquoPolydatin inhibits cell proliferationinvasion and migration and induces cell apoptosis in hepato-cellular carcinomardquo Brazilian Journal of Medical and BiologicalResearch vol 51 no 4 2018

[62] Y Zhang Y Xiong J Zhou N Xin Z Zhu and Y WuldquoFoxO1 expression in osteoblasts modulates bone formationthrough resistance to oxidative stress in micerdquo Biochemical andBiophysical Research Communications vol 503 no 3 pp 1401ndash1408 2018

[63] M Malumbres andM Barbacid ldquoCell cycle CDKs and cancera changing paradigmrdquo Nature Reviews Cancer vol 9 no 3 pp153ndash166 2009

[64] H Wang B N Nicolay J M Chick et al ldquoThe metabolicfunction of cyclin D3-CDK6 kinase in cancer cell survivalrdquoNature vol 546 no 7658 pp 426ndash430 2017

[65] S Kamarajugadda J R Becker E A Hanse et al ldquoCyclin D1represses peroxisome proliferator-activated receptor alpha andinhibits fatty acid oxidationrdquo Oncotarget vol 7 no 30 pp47674ndash47686 2016

[66] W-J Cao K Wu C Wang and D-M Wan ldquoPolydatin-induced cell apoptosis and cell cycle arrest are potentiated byJanus kinase 2 inhibition in leukemia cellsrdquoMolecularMedicineReports vol 13 no 4 pp 3297ndash3302 2016

[67] N Funamizu C R Lacy K Fujita et al ldquoTetrahydrouridineinhibits cell proliferation through cell cycle regulation regard-less of cytidine deaminase expression levelsrdquo PLoS ONE vol 7no 5 2012

[68] Y Liu Y-L Guo S-J Zhou et al ldquoCREB is a positive transcrip-tional regulator of gamma interferon in latent but not activetuberculosis infectionsrdquo Clinical and Vaccine Immunology vol17 no 9 pp 1377ndash1380 2010

[69] A Chhabra H Fernando G Watkins R E Mansel and WG Jiang ldquoExpression of transcription factor CREB1 in humanbreast cancer and its correlation with prognosisrdquo OncologyReports vol 18 no 4 pp 953ndash958 2007

[70] S Chen J Tao F Zhong et al ldquoPolydatin down-regulates thephosphorylation level of Creb and induces apoptosis in humanbreast cancer cellrdquo PLoS ONE vol 12 no 5 2017

[71] S Tian Y Yang X Liu and Q Xu ldquoEmodin attenuatesbleomycin-induced pulmonary fibrosis via anti-inflammatoryand anti-oxidative activities in ratsrdquo Medical Science Monitorvol 24 pp 1ndash10 2018

[72] L Li X Song Z Yin et al ldquoThe antibacterial activity and actionmechanism of emodin from Polygonum cuspidatum againstHaemophilus parasuis in vitrordquo Microbiological Research vol186-187 pp 139ndash145 2016

[73] W-F Lin C Wang and C-Q Ling ldquoResearch progress inanti-tumor effect of emodinrdquo China journal of Chinese materiamedica vol 40 no 20 pp 3937ndash3940 2015

[74] J-A Shin J-H Shim J-G Jeon et al ldquoApoptotic effectof Polygonum Cuspidatum in oral cancer cells through theregulation of specificity protein 1rdquo Oral Diseases vol 17 no 2pp 162ndash170 2011

[75] S-G Choi J Kim N-D Sung et al ldquoAnthraquinones Cdc25Bphosphatase inhibitors isolated from the roots of PolygonummultiflorumThunbrdquoNatural Product Research (Formerly Natu-ral Product Letters) vol 21 no 6 pp 487ndash493 2007

[76] S C Kang C M Lee E S Choung et al ldquoAnti-proliferativeeffects of estrogen receptor-modulating compounds isolatedfrom Rheum palmatumrdquo Archives of Pharmacal Research vol31 no 6 pp 722ndash726 2008

[77] M S Lee E Y Cha J Y Sul I S Song and J Y KimldquoChrysophanic acid blocks proliferation of colon cancer cells byinhibiting EGFRmTOR pathwayrdquo Phytotherapy Research vol25 no 6 pp 833ndash837 2011

Stem Cells International

Hindawiwwwhindawicom Volume 2018


MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine


Behavioural Neurology

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


Resveratrol

OH

OH

HOOH

Antineoplasticingredients

OH OH

O

O

HO

Emodin

OH OH

OO

O

Chrysophanic acid

Polydatin

OH

OH

O

OHOH

OOH

HO（2C

Figure 1 Antitumor components of Polygonum cuspidatum Resveratrol C14H12O3 trans-3t4 and 5-Trihydroxystilbene Poly-datin C20H22O8 341015840-5-Trihydroxystilbene-3-beta-D-glucopyranoside Emodin C15H10O5 and 138-Trihydroxy-6-methylanthraquinoneChrysophanic acid C15H8O6 45-dihydroxy-910-dioxo-9 and 10-dihydroanthracene-2-carboxylic acid

Metabolism

Immunity Invasion

Metastasis

Apoptosis

Gutmicrobiota

Proliferation

Cancerpain Resveratrol

Figure 2 Antitumor effect of resveratrol Resveratrol not only acts on tumor cells themselves but also regulates human immunity andmicroenvironment Moreover it can improve the life quality of cancer patients by improving cancer pain

growing number of researches have shown that the effect ofPolygonum cuspidatum and its active ingredients in cancertreatment is remarkable Here we will review the researchprogress of active components of Polygonum cuspidatumin tumor diseases therapy mainly including resveratrolpolydatin emodin and chrysophanic acid (Figure 1)

21 Antitumor Activity of Resveratrol Resveratrol wasoriginally extracted from the roots of Polygonumcuspidatum which is also found in red wine grapesand peanuts [6] Many health benefits have been linkedto it including antitumor [7] anti-inflammation [6]antioxidation [8] immunoregulation [9] and even gutmicrobiota-regulation [10] Currently resveratrol hasattracted attention of researchers for its antitumor effect ina variety of human cancer cell lines through the regulationof various molecular targets [11] Its antitumor roles

cover almost all aspects of cancer including tumor cellproliferation invasion metastasis apoptosis [7] immunity[12] metabolism [13] and intestinal flora [14] (Figure 2)

211 Resveratrol and Tumor Proliferation Invasion Metas-tasis and Apoptosis In the past few years resveratrol hasbeen found to play important roles in tumor progressionincluding proliferation invasion metastasis and apoptosis(Figure 3) Resveratrol is a potent natural activator of sirtuin-1 (SIRT1) a nuclear substance associated with the histonedeacetylases class III [15] Moreover resveratrol can inhibitepithelial mesenchymal transition (EMT) associated cancercell invasion and migration through the inhibition of the PI-3KAktNF-B TGF-1205731 and hedgehog signaling pathway[16ndash18] As our previous experiments in vitro have shownTGF-1205731-induced EMT promoted the invasion and metastasisof colorectal cancer but resveratrol could inhibit the invasive


InvasionMetastasis

mRNASTAT-3

cytotoxicity




FAK-ICYTD

OH

HOOH

RES





















Immunity

Spleen

CD4+ T cells

Gutmicrobiota

Function

Integrity

Microbiotica


Metabolism

Glucose

PKM2

PFK

OH

HOOH

RES


Inflammation

SOCS1


MAPK STAT1STAT3

miR-155

STAT SOCS1

OH

HOOH

RES

ER







Neuro-Inflammation

Restrain

NR1NR2B


CX3CR1

Cancer pain

OH

HO

OH

RES









Creb

BaxBcl-2

BaxBcl-2

ROS

Polydatin

Breast cancer cells

Lung cancercells

CNE cells

AMC-HN-8Hep-2 cells

Caco-2cells

Osteosarcomacells

OH

OH

O

OH

OHO

OH

HOHC






HO

O

O

HO

OH HO OH

OHOO

O

Oral cancer cells














Acknowledgments


References




















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















InvasionMetastasis

mRNASTAT-3

cytotoxicity




FAK-ICYTD

OH

HOOH

RES





















Immunity

Spleen

CD4+ T cells

Gutmicrobiota

Function

Integrity

Microbiotica


Metabolism

Glucose

PKM2

PFK

OH

HOOH

RES


Inflammation

SOCS1


MAPK STAT1STAT3

miR-155

STAT SOCS1

OH

HOOH

RES

ER







Neuro-Inflammation

Restrain

NR1NR2B


CX3CR1

Cancer pain

OH

HO

OH

RES









Creb

BaxBcl-2

BaxBcl-2

ROS

Polydatin

Breast cancer cells

Lung cancercells

CNE cells

AMC-HN-8Hep-2 cells

Caco-2cells

Osteosarcomacells

OH

OH

O

OH

OHO

OH

HOHC






HO

O

O

HO

OH HO OH

OHOO

O

Oral cancer cells














Acknowledgments


References




















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






























Immunity

Spleen

CD4+ T cells

Gutmicrobiota

Function

Integrity

Microbiotica


Metabolism

Glucose

PKM2

PFK

OH

HOOH

RES


Inflammation

SOCS1


MAPK STAT1STAT3

miR-155

STAT SOCS1

OH

HOOH

RES

ER







Neuro-Inflammation

Restrain

NR1NR2B


CX3CR1

Cancer pain

OH

HO

OH

RES









Creb

BaxBcl-2

BaxBcl-2

ROS

Polydatin

Breast cancer cells

Lung cancercells

CNE cells

AMC-HN-8Hep-2 cells

Caco-2cells

Osteosarcomacells

OH

OH

O

OH

OHO

OH

HOHC






HO

O

O

HO

OH HO OH

OHOO

O

Oral cancer cells














Acknowledgments


References




















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Immunity

Spleen

CD4+ T cells

Gutmicrobiota

Function

Integrity

Microbiotica


Metabolism

Glucose

PKM2

PFK

OH

HOOH

RES


Inflammation

SOCS1


MAPK STAT1STAT3

miR-155

STAT SOCS1

OH

HOOH

RES

ER







Neuro-Inflammation

Restrain

NR1NR2B


CX3CR1

Cancer pain

OH

HO

OH

RES









Creb

BaxBcl-2

BaxBcl-2

ROS

Polydatin

Breast cancer cells

Lung cancercells

CNE cells

AMC-HN-8Hep-2 cells

Caco-2cells

Osteosarcomacells

OH

OH

O

OH

OHO

OH

HOHC






HO

O

O

HO

OH HO OH

OHOO

O

Oral cancer cells














Acknowledgments


References




















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Neuro-Inflammation

Restrain

NR1NR2B


CX3CR1

Cancer pain

OH

HO

OH

RES









Creb

BaxBcl-2

BaxBcl-2

ROS

Polydatin

Breast cancer cells

Lung cancercells

CNE cells

AMC-HN-8Hep-2 cells

Caco-2cells

Osteosarcomacells

OH

OH

O

OH

OHO

OH

HOHC






HO

O

O

HO

OH HO OH

OHOO

O

Oral cancer cells














Acknowledgments


References




















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Creb

BaxBcl-2

BaxBcl-2

ROS

Polydatin

Breast cancer cells

Lung cancercells

CNE cells

AMC-HN-8Hep-2 cells

Caco-2cells

Osteosarcomacells

OH

OH

O

OH

OHO

OH

HOHC






HO

O

O

HO

OH HO OH

OHOO

O

Oral cancer cells














Acknowledgments


References




















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of


























Acknowledgments


References




















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















Documents

RiewArticle - Hindawi Publishing Corporationdownloads.hindawi.com/journals/ecam/2018/2313021.pdf · in tumor diseases therapy, mainly including resveratrol, polydatin,emodin,andchrysophanicacid(Figure)