Review Article Chinese Medicines Induce Cell Death: The ...downloads.hindawi.com/journals/bmri/2014/530342.pdf · Review Article Chinese Medicines Induce Cell Death: The Molecular

Review ArticleChinese Medicines Induce Cell Death The Molecular andCellular Mechanisms for Cancer Therapy

Xuanbin Wang12 Yibin Feng1 Ning Wang1 Fan Cheung1 Hor Yue Tan1

Sen Zhong2 Charlie Li3 and Seiichi Kobayashi4

1 School of Chinese Medicine The University of Hong Kong 10 Sassoon Road Pokfulam Hong Kong2 Laboratory of ChineseHerbal PharmacologyHubei Key Laboratory ofWudang Local ChineseMedicine Research School of PharmacyHubei University of Medicine Shiyan Hubei 442000 China

3 California Department of Public Health 850 Marina Bay Parkway G365 Richmond CA 94804 USA4Faculty of Healthy Science Hokkaido University Kita 15 Nishi 7 Kita-ku Sapporo Japan

Correspondence should be addressed to Yibin Feng yfenghkuhk

Received 24 May 2014 Accepted 23 July 2014 Published 14 October 2014

Academic Editor Gagan Deep

Copyright copy 2014 Xuanbin Wang 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

Chinese medicines have long history in treating cancer With the growing scientific evidence of biomedical researches and clinicaltrials in cancer therapy they are increasingly accepted as a complementary and alternative treatment One of the mechanisms isto induce cancer cell death Aim To comprehensively review the publications concerning cancer cell death induced by Chinesemedicines in recent years and provide insights on anticancer drug discovery from Chinese medicines Materials and MethodsChinesemedicines (includingChinesemedicinal herbs animal parts andminerals) were used in the studyThekeywords includingldquocancerrdquo ldquocell deathrdquo ldquoapoptosisrdquo ldquoautophagyrdquo ldquonecrosisrdquo and ldquoChinesemedicinerdquo were used in retrieval of related information fromPubMed and other databasesResultsThe cell death induced byChinesemedicines is described as apoptotic autophagic or necroticcell death and other types with an emphasis on their mechanisms of anticancer actionThe relationship among different types of celldeath induced by Chinese medicines is critically reviewed and discussed ConclusionsThis review summarizes that CMs treatmentcould induce multiple pathways leading to cancer cell death in which apoptosis is the dominant type To apply these preclinicalresearches to clinic application will be a key issue in the future

1 Introduction

Cancer is one of the leading causes of death in the worldGLOBOCAN data revealed that approximately 127 millionnew cases of cancers have been diagnosed and 76 milliondeaths were attributed to cancers in 2008 [1] In these life-threatening cancers the causes are diverse and complexand are only partially understood the reasons why they aredifficult to cure might be due to the complicated cancerhallmarks sustaining proliferative signaling resisting celldeath inducing angiogenesis enabling replicative immortal-ity activating invasion and metastasis evading growth sup-pressors irregulating cellular energetic genome instabilityand mutation as well as tumor-promoting inflammation andavoiding immune destruction among which resisting cell

death is the intracellular or external factors-triggered tumoraction to escape from insult [2]

Cell death has conventionally been divided into threetypes apoptosis (Type I) autophagy (Type II) and necrosis(Type III) [3 4] Apoptosis Type I programmed cell death(PCD) is a normal response of a physiological processit becomes a pathological trait in many diseases includ-ing cancers when apoptosis is irregulated It is also themajor type of cell death induced by most of the frontlinechemotherapeutic agents [3 5 6] In the process of apoptoticcell death cells have altered morphology such as blebbingcell shrinkage nuclear fragmentation and chromatin con-densation Morphological features of Type II cell death aredifferent from those of apoptosis in which formation ofautophagosome and cytolysis of autophagosome-lysosome

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 530342 14 pageshttpdxdoiorg1011552014530342

2 BioMed Research International

fusion involve the degradation of the components in cancercells through the lysosomal machinery [7] Type III cell deathis a necrotic process whose typical characteristics of necrosisinclude disruption of plasma membrane and induction ofinflammation that have been conventionally regarded as anaccidental uncontrolled cell death However recent studiesfound that necrosis could be under control as it sharedthe same stimuli (cytokines pathogens ischemia heat andirradiation) signaling pathways (death receptors kinase cas-cades and mitochondrial) and protective mechanisms (Bcl-2Bcl-x heat shock protein) as apoptosis [5 8] Besides thesethree types of cell death several other cell death pathwayshave been elucidated [4 9ndash12] Since these distinct cell deathshave different subroutines the Nomenclature Committee onCell Death (NCCD) has proposed a set of recommendationsto define cell deaths based on the biochemical and functionalcondensation in 2012 [9]

Since many of the clinical anticancer drugs are originallyfrom natural sources such as vinca alkaloids and taxanes upto date some studies have focused on the herbal medicinalproducts especially Chinese medicines (CMs includingplants animals and minerals) [13ndash18] Natural productsare important sources of anticancer lead molecules Manysuccessful anticancer drugs come from natural productsMore are still under clinical trialsThe aim is to develop novelanticancer drugs derived from natural products especiallyfrom CMs More critical systematic studies on cellular andmolecular therapeutic principle of anticancer natural prod-ucts from CMs in cancer cell deaths need to be conducted

In this review we retrieved the relevant publications fromPubMed and other databases to summarize the actions ofCMs involved in inducing cancer cell death in vitro andin vivo Besides clinical applications other novel cell deathpathways and the relevance of CMs in these fields are alsodiscussed here

2 CMs Induce CancerCell Death and Their UnderlyingMechanisms

21 CMs Induce Apoptotic Death in Human Cancer CellsBoth intrinsic and extrinsic pathways involve activation ofapoptosis by CMs in human cancer cells The CM-initiatedapoptotic cell death is mainly dependent on the activation ofcaspase cascade There are two types of apoptotic caspasesinitiator (apical) caspases and effector (executioner) caspasesInitiator caspases (eg CASP2 CASP8 CASP9 and CASP10)cleave inactive proforms of effector caspases thereby activat-ing them Initially caspases are cysteine-aspartic proteases orcysteine-dependent aspartate-directed proteases in inactiveformsThey are cleaved by interacting special molecules suchas Apaf-1 (apoptotic protease-activating factor-1) FasCD95or tumor necrosis factor 120572 (TNF120572) when apoptosis is inducedin cells [9 132] Extrinsic apoptosis depends on caspaseactivation while intrinsic apoptosis is either in caspase-dependent or -independentmanner [9 133] CMs can activatecancer cell death extrinsically intrinsically or both thereforethe mechanisms of CMs inducing cancer apoptotic cell death

have been more diversified Table 1 summarizes the generalinformation ofCMs inducing apoptotic cell deathThe typicalexamples are in Table 1 and Figure 1

211 CMs Induce Apoptosis Intrinsically CMs-inducedintrinsic apoptosis mainly requires the activation of caspasesCMs can also induce apoptotic cell death by caspase-independent manner because some types of cancer cellscan ablate the expression of caspases In addition even incaspase-proficient cancer cells CMs treatment can activateall types of intrinsic apoptosis eventually leading to potentcancer cell death

Ursolic acid (UA) is an active ingredient in several CMssuch as Oldenlandia diffusa (Willd) Roxb (Chinese nameBaihuasheshecao) Ligustrum lucidum WTAiton (Chinesename Nuzhen) and Eriobotrya japonica (Thunb) Lindl(Chinese name Pipa) Previous studies showed that UAcould induce cancer cell death by enabling the caspase-dependent pathway It was reported that UA activatedcaspase-3 and caspase-9 in human prostate cancer cellsRC-58ThSA4 [32] UA binding with oleanolic acid couldelevate the caspase-3 activity in human liver cancer cellsHuh7 HepG2 Hep3B and HA22T [35] Its antitumoreffect was also observed in xenograft model The resultsof positron-emission tomography-computed tomography(PET-CT) imaging indicated that proliferation of tumor cellsdeclined after UA treatment in vivo [34 134] Generally themechanism of CMs to cause intrinsic cell death in cancer iscaspase-dependent CMs induced the release of cytochromec from mitochondria [23] which facilitated the activationof apoptotic protease-activating factor-1 (Apaf-1) and formsApaf-1 apoptosome that bound to caspase-9 through CARD-CARD (caspase recruitment domain) interactions to forma holoenzyme complex [135 136] The complex cleavedcaspase-3 to produce a caspase cascade resulting in celldeath [94 136]Themechanisms of some representative CMsinducing cancer intrinsic cell death are illustrated in Figure 1

Apart from caspase-dependent cell death CMs couldinitiate apoptosis in both caspase-dependent and caspase-independent manners The main biochemical pathway ofcaspase-independent cell apoptosis was elucidated as theresults of release of mitochondrial intermembrane space(IMS) proteins and inhibition of respiratory chain In thiscontext apoptosis-inducing factor (AIF) and endonucleaseG (Endo G) relocated to the nucleus and mediate large-scale DNA fragmentation The serine protease a high tem-perature requirement protein A2 (HTRA2) cleaved manycellular substrates including cytoskeletal proteins as well[9] Gypenosides (Gyp) derived from Gynostemma penta-phyllum (Thunb) Makino (Chinese name Jiaogulan) couldsuppress the growth of WEHI-3 cells in vitro and in vivothrough caspase-dependent and -independent apoptosisGyp inhibited Bcl-2 increased Bax and induced the releaseof cytochrome c and depolarization of mitochondrial mem-brane potential (Δ120595) and stimulated the activities of caspase-3 and caspase-8 suggesting that Gyp triggered caspase-dependent cell death Gyp also induced the generationof ROS and stimulated the release of AIF and Endo G

BioMed Research International 3

Table 1 Pure compounds and fractions of CMs inducing cancer cell death and the pathways

Compounds ResourceChinese name Cell death pathwayArtemisinins Artemisia annua Lqinghao Apoptosis necrosis [19ndash21]

Tanshinone IIAcryptotanshinone Salvia miltiorrhiza BungeDanshen

Tanshinone IIA apoptosis[22 23] autophagy [24]cryptotanshinone apoptosis [25]

Pseudolaric acid B Pseudolarix kaempferi GordonJinqiansong Autophagy [26] apoptosis[27 28]

Ursolic acid

Oldenlandia diffusa (Willd) RoxbBaihuasheshecao

Ligustrum lucidumWTAitonN 120592zhen Eriobotryajaponica (Thunb) LindlPipa

Autophagy [29 30] apoptosis[31ndash35]

Triptolide Tripterygium wilfordiiHook fLeigongtengBoth apoptosis and autophagy[36] autophagy [37] apoptosis[38]

Oridonin Rabdosia rubescens (Hemsl) HaraDonglingcaoAutophagy [39 40] bothautophagy and apoptosis[39 41 42] apoptosis [43 44]

120573-Elemenecurcumol Curcuma wenyujin YHChen and CLingEzhu 120573-Elemene apoptosis [45ndash49]

Curcumol apoptosis [50]

Rp1 Rg3 Rh2 Rk1 Rg5etc Panax ginseng CAMeyRenshen

Extracts apoptosis [51ndash55]Rg3 apoptosis (via decrease ofPim-3 and pBad NF-120581Binactivation)[56 57]Rh2 apoptosis andparaptosis-like cell death[42 58 59] apoptosis [60]Rp1 paraptosis [61] apoptosis[62]KG-135 with etoposide (formulaof Rk1 Rg3 and Rg5) apoptosis[63]

Polyphyllin D Paris polyphylla SmChong Lou Apoptosis [64 65]

Gypenosides Gynostemma pentaphyllum (Thunb)MakinoJiaogulan Apoptosis [66]

Baicalin wogoninoroxylin A baicalein Scutellaria baicalensis GeorgiHuangqin Apoptosis [67ndash75]

Hesperidin Citrus reticulate BlancoChenpi Apoptosis [76ndash78]Glycyrrhizin18120573-glycyrrhetinic acid Glycyrrhiza glabra LGancao Apoptosis [79ndash81]

Eugenol Areca catechu LBinlang Apoptosis [82]11015840S-11015840-acetoxyeugenolacetate Alpinia conchigera GriffJiebianshanjiang Apoptosis (via NF-120581B

inactivation)[83]

Catechins(-(epicatechin-3-gallate(EGCG)) polyphenols

Camellia sinensis (L) KuntzeCha

EGCG autophagy[42 58 59 84] apoptosis[74 75] anoikis [85] parthanatos[86]catechin apoptosis [87]polyphenols (GrTP) apoptosis[88ndash90]

Cryptocaryone Cryptocarya concinnaHanceTunan Apoptosis [91]Curcumin Curcuma longa LJianghuang Apoptosis [92 93]Emodin Rheum palmatum LDahuang Apoptosis [45ndash48 94]

Aloe emodin Rheum palmatum LDahuangPolygonum cuspidatum Siebold amp ZuccHuzhang Apoptosis [95 96]

Silibinin Silybum marianum (L) GaertnShuifeiji Apoptosis [97ndash100]autophagy [46 101]


Table 1 Continued

Compounds ResourceChinese name Cell death pathwayGambogic acid Garcinia hamburgy Hook fTenghuang Apoptosis [102ndash104]

Shikonin Lithospermum erythrorhizon Siebold amp ZuccZicao Apoptosis [105]necroptosis [106 107]

Berberine Coptischinensis FranchHuanglianApoptosis [108 109]autophagy [110 111] necrosis[112] anoikis [113]

Camptothecin Camptotheca acuminate DecneXishu Apoptosis [114]Tetrandrinefangchinoline Stephania tetrandra S MooreFangji Tetrandrine apoptosis [50 115]

fangchinoline autophagy [34]

Matrineoxymatrine Sophora flavescens AitKushen

Matrine apoptosis [116 117]autophagy [118ndash120]oxymatrine apoptosis [121]

Herbal extracts Zanthoxylum ailanthoides Siebold amp ZuccShizhuyu Apoptosis [122]Pharicin A Isodon amethystoides (Benth) H HaraXiangchacai Mitotic catastrophe [123]

Casticin Vitex rotundifolia LfManjing Mitotic catastrophe andapoptosis [124]

Selenium-rich aminoacids silkworm pupasChanyong Apoptosis [125]

Arsenic trioxide PishuangNecrosis [126] apoptosis[45ndash48 127ndash130]autophagy [131]

resulting in caspase-independent cell death [66] Silibinin(from Shuifeiji silybummarinaum (L) Gaenrt) was reportedto stimulate the release of HTRA2 and AIF in bladdercarcinoma cell line 5637 as well as cytochrome c and activatecaspase-3 Thus silibinin could induce bladder cell death inboth caspase-dependent and -independent manners [100](Figure 1 Table 1)

There are some relationships between CMs and intrinsicdeath stimuli for example Scutellaria one of the mostpopular CM herbal remedies used in China and severaloriental countries for treatment of inflammation bacterialand viral infections and it has been shown to possessanticancer activities in vitro and in vivo in mouse tumormodels [137 138] The bioactive components of Scutellariawere confirmed to be flavonoids [138 139] Chrysin is anatural flavone commonly found in honey that has beenshown to be an antioxidant and anticancer agent [140]Several studies showed that Chrysin and Apigenin couldpotentiate the cytotoxicity of anticancer drugs by depletingcellularGSH an important factor in antioxidant defense [141ndash143] A 50ndash70 depletion of intracellular GSH was observedin prostate cancer PC-3 cells after 24 h of exposure to 25120583MChrysin or Apigenin [141 144]

212 CMs Induce Apoptosis Extrinsically Since extrinsicapoptosis of cancer cells is initiated by binding of death recep-tors and their ligands the death receptors may function assignaling gateway in which FasCD95 ligands (FasLCD95L)and some cytokines such as TNF120572 and TNF superfamilymember 10 (TNFSF10 also known as TRAIL) play greatroles in inducing apoptosis These lethal cytokines activateFas-associated protein with a ldquodeath domainrdquo (FADD) and

thereby activate caspase-810 caspase-3 caspase-67 to a cas-cade apoptosis response Matrine an alkaloid purified fromSophora flavescens Ait (Chinese name Kushen) inducesthe apoptosis of gastric carcinoma cells SGC-7901 A studyusing MTT assay showed that matrine inhibited SGC-7901cells proliferation in dose- and time-dependent mannersFurthermore the levels of both Fas and FasL were foundto be upregulated after matrine treatment which resultedin apoptotic cell death by the activation of caspase-3 [116]Other CMs involved in the induction of extrinsic apoptosisincluded oridonin (from Donglingcao Rabdosia rubescens(Hemsl) Hara) [44] polyphenols from green tea [88 89]and glycyrrhizin (from gancao Glycyrrhiza glabra L) [81] aslisted in Table 1

213 CMs Induce Both Intrinsic and Extrinsic ApoptosisSome of CMs exhibit a complex nature by inducing bothintrinsic and extrinsic apoptosis Kim et al found that UAinduced the expression of Fas and cleavage of caspase-3 andcaspase-8 as well as caspase-9 and decreased its Δ120595 Othereffects such as Bax upregulation Bcl-2 downregulation andthe release of cytochrome c to the cytosol frommitochondriawere caused by UA treatment [31] (Figure 1 Table 1)

22 CMs Induce Autophagic Cancer Cell Death Autophagiccell death is characterized with a massive cytoplasmic vac-uolization resulting in physiological cell death which isparticularly induced when cells are deficient in essentialapoptotic modulators such as Bcl-2 family and caspasesSome of the CMs induce autophagy via several signalingpathways that mediates the downregulation of mammaliantarget of rapamycin (mTOR) and upregulation of Beclin-1


Extrinsic pathway

FasL

FADD

Pro

Caspase-810

Pro Caspase-3

Caspase-3

Caspases 6 7

Mitochondria

BaxBak

Bcl-2Bcl-xL

Apaf-1

cFLIPs cIAPs

Nucleus

DNA fragmentation

IAPs

IMS proteinsendo G

AIF

SmacDIABLO

CytC

TRAIL-R1

FasCD95APO-1

AE ART BAI BL BER CUL CUR RGCG ELEMO EUG HES HET OR PD SIL GA GC GS GY TAN UA MAT OX

Intrinsic pathway (caspase-independent)

PARP

P53

DR45

DR45

Apoptosis

AE BER CRY GC OR SIL TAN green tea EMO MAT

BER EMO AE SIL CUR GS UA WO EGCG CAM CAT CRP

ACE BER GA GC UA CRP

AE

ATO

CU

REM

O M

ATCRP

CAM BER

CUR

ES SRA ATO

Intrinsic pathway (caspase-dependent)

Caspase-810

TNF-120572

TRAIL-R2

CRP

Caspase-9

ART BAI BER GC BL CUREL EMO GA GS GY PABOR PD SHI SIL TAN TETUA WO HES EUG EGCGCAT CUR CAM ES

AE BER CUR EL EMO GA

GS GY OR PD SHI SIL TAN

TET UA GC EUG CAT MAT

ES ATO

AE BER BL EL CAM

EMO GA GY HES

OR ORA PD TET

OX TH WO

CAT CUR

HSP27

BER GY SIL AE ES

SHITET AE B

ER EMO

GA OX A

TO

AE BER EMO GA SILSurvivinHSP7090

AE

AR BAI GC TET W

O

ACE EGCG CURAE BER EMO SHI

SIL CAM MAT ATO

AE EL WOGC TH EL ES

Figure 1 Schematic diagram of the mechanisms of CMs-induced cancer apoptosis ACE 11015840S-11015840-acetoxyeugenol acetate AE aloe emodinART artemisinins ATO arsenic trioxide BAI baicalin BL baicalein BER berberine CAM camptothecin CAT catechins CRPcryptocaryone CRY cryptotanshinone CUR curcumin CUL curcumol EL 120573-elemene EGCG (-)epicatechin-3-gallate and polyphenolsEMO Emodin ES extract of shizhuyu EUG eugenol GA gambogic acid GC gancaoGSGinsengGY gypenosidesHES hesperidinHEThesperetin MAT matrine OR oridonin ORA oroxylin A OX oxymatrine PD polyphyllin D PAB pseudolaric acid B SHI shikonin SILsilibinin SRA selenium-rich amino acids TAN tanshinone IIA TET tetrandrine TH total huangqin glucosides TRI triptolide UA ursolicacid WO wogonin

[4 5 12] (Figure 2) We previously reported that fangchino-line (isolated from Fangji Stephenia tetrandra S Moore) trig-gered autophagy in a dose-dependent manner on two humanhepatocellular carcinoma cell lines HepG2 and PLCPRF5Blocking fangchinoline-induced autophagy process wouldalter the pathway of cell death leading to apoptosis thus celldeath was an irreversible process induced by fangchinoline[34] Cheng et al reported that the exposure of murinefibrosarcoma L929 cells to oridonin led to the release ofcytochrome c translocation of Bax and generation of ROSAdditionally oridonin induced autophagy in L929 cellsthrough p38 andNK-120581B pathways Autophagy occurred afteroridonin treatment and blocking autophagy caused apoptosis[39 40] These observations suggested that autophagic celldeath governed the cell fate upon CMs treatment Generalinformation of CMs inducing autophagic cell death is sum-marized in Table 1 Figure 2 further illustrates the mecha-nisms of some representative CMs inducing autophagic celldeath

23 CMs Induce Necrotic Cancer Cell Death Necrosis isclassified as nonprogrammed cell death in the absence ofmorphological traits of apoptosis or autophagy This phe-nomenon gives rise to ldquouncontrolledrdquo cell death loss of ATP

and membrane pumps [4] In contrast to these featuresrecent study showed that necrosis exhibited its regulatedcharacteristic in other words necroptosis [9] This processinvolved alkylating DNA damage excitotoxins and ligationof death receptors under some conditions which dependedon the serinethreonine kinase activity of RIP1 target of anew cytoprotective agent necrostatins Others that affectedthe execution of necroptosis were named cyclophilin D poly(ADP-ribose) polymerase 1 (PARP-1) and AIF [145] Severalresearches on CMs have focused on the study of necrosis ornecroptosis Shikonin a component extracted from Lithos-permum erythrorhizon Siebold amp Zucc (Zicao) has beenfound to induce necrotic cell death in MCF-7 and HEK293Han et al reported that cell death pathway of shikonin-treated cells was different from either apoptosis or autophagiccell death in which loss of plasma membrane integrity wasone of the morphology of necrotic cell death but loss of Δ120595and elevation of ROS did not critically contribute to cell deathdue to the protection by necrostatin-1 [106 107] ROS andCa2+ elevated permeability transition pore complex- (PTPC-) dependent mitochondrial permeability transition (whichwas also induced by RIP1) while necrostatin-1 specificallyprevented the cells from necroptosis In summary shikonincould induce cancer cells into necroptosis


ORIL-3

JNK

Atg3Ulk1

FIP200

PI3K

Mitochondria

mTOR

Nucleus

Akt

Autophagy

Bif

IL-3R

IKK

Bid

Apoptosis

Prosurvival genes

IKK

BER EGCG PAB TRI Beclin-1

ATO BER UA

TRI ATOOR

FA

Bcl-2Bcl-xL

TNF-120572

NF-120581BTRAIL-R1 DR45

DR45TRAIL-R2

ROS

SIL

PAB

Caspases

UVRAG

SIL

AMPK

Figure 2 Schematic diagram of the mechanisms of the CMs for cancer autophagy death AE aloe emodin ATO arsenic trioxide BERberberine EGCG (-)epicatechin-3-gallate and polyphenols FA fangchinoline OR oridonin PAB pseudolaric acid BSIL silibinin TRItriptolide UA ursolic acid

Arsenic trioxide another popular CM (Chinese namePishuang) also induced necrosis in the dose of 1mgkgaccompanied by a sharp decrease of proliferation indexin HCC cells [126] Mercer et al reported that treatmentof artesunate (50 120583m 48 h) an artemisinin from Artemisiaannua L (Chinese name Qinghao) induced 24 plusmn 9 ofnecroticlate apoptotic in HeLa cells and 67 plusmn 21 necroticin HeLa 1205880 cells These data suggested that induced necrosiswas associated with low levels of ATP and defective apoptoticmechanisms in some cancer lines [21] Table 1 shows generalinformation of CMs-induced necrotic cell death Figure 3illustrates the mechanisms of some representative CMs-induced necrotic cell death

3 Discussion

As one of the typical cancer hallmarks cell death has attractedgreat attention in recent years and the study of this biologicalprocess with intervention of CMs will explore a novel way totreat cancers clinically However many CMs have not beenapproved for clinical use yet To further investigate the effi-cacy and toxicity of CMs further researches and clinical trialsare necessary In addition a lot of CMs have been directly

used as composite formula in cancer clinics according toChinese medicinersquos theories for centuries However limitedcomposite formula-induced anticancer action via cell deathpathway is known and only few researches have been con-ducted from in vitro study for example Huang-lian-jie-du-tang (Japanese name oren-gedoku-to) induced apoptotic celldeath in humanmyeloma cells [146] HepG2 and PLCPRF5cells [147] More studies on composite Chinese medicineformula with good quality control would be needed at themolecular and cellular level

As mentioned above CM may exhibit integrated oradditive anticancer effect through two or more subpathwaysTriptolide (from Leigongteng Tripterygium wilfordii Hookf) could induce both caspase-dependent and -independentapoptotic cell death by activating caspase-3 caspase-8 andcaspase-9 and Bax but decreasing Bcl-2 [36ndash38 113 148ndash152]These studies indicated that CMs might function on multiplemodes in cancer cells which need further studies [12 153](Figure 1) With regard to cell deaths through integratedor additive effect we have conducted a study to explorehow berberine (from Huanglian Coptis chinensis Franch)induced cell death in human liver cancer cells HepG2and MHCC97-L We found that the chemical induced bothapoptosis and autophagy in which autophagy accounts for


FasL

FADD

TRADD

JNK

Nucleus

DNA

PRAP

Necrosisnecroptosis

FADD

RIP3

RIP1

MitochondriaSHI ART ATO BER

Necrostatins

AIF

TNF-120572

TRAIL-R1 DR45

DR45TRAIL-R2

FasCD95APO-1

Ca2+ ROS

Figure 3 Schematic diagram of the mechanisms of CMs for cancer necroticnecroptotic death ART artemisinins ATO arsenic trioxideBER berberine SHI shikonin

30 of berberine-induced HepG2 cell death while apoptosiswas responsible for the most contribution to liver cancercell death With regard to the underlying mechanism ofberberine-induced autophagic and apoptotic cell death ourdata demonstrated it could induce Bax activation forma-tion of PTPC reduction of Δ120595 and release of cytochromec and Beclin-1 [111] Similar to apoptosis autophagy andnecrosisnecroptosis affect PTPC ROS Ca2+ Bcl-2 BaxAIF PARP and other cytokines during programmed celldeath it was reported that berberine induced necrosis inB16 cells [112] But it is unknown whether berberine caninduce programmed necrosis in HepG2 The cross talkamong the three cell death pathways may lead to therapeuticimplications For instance the selective inhibition of necrosisor apoptotic cell deathmay defend inflammation and therebyreduce subsequent tissue damage Besides it may serve as anovel therapeutic strategy by inducing necrotic cell death onapoptosis resistant cancer cells [109 145]

The effectiveness of cancer chemotherapy significantlydepends on apoptosis in cancer cells while the significance ofautophagy and necrosis in cancer therapy needs to be furtherclarified Several reports showed that some CMs inducedautophagy and inhibited cell apoptosis [30 37 45ndash48] Incontrast some may induce autophagy leading to apoptosis[36 41 111] In this context autophagy might act as a house-keeper which eliminated abnormal proteins and recyclesmaterials during cell starvation [7 154] Cell death pathwaycould switch to apoptosis or necrosis by inhibiting autophagy[4 9] However themolecularmechanism between apoptosisand programmed necrosis (or necroptosis) is still unclear

In addition to the above three types of cell death there areother new types of cell death Ginsenoside Rh2 (From Ren-shen) exhibited significant effects on cell death in colorectalcancer cells HCT116 and SW480 Besides inducing apoptosisthrough activation of p53 pathway Ginsenoside Rh2 alsoincreased visible cytoplasmic vacuolization in HCT116 cellswhich were blocked by cycloheximide (CHX) a proteinsynthesis inhibitor Due to the characteristic of paraptosis asvisible cytoplasmic vacuolization without disruption of thecell membrane [155 156] Ginsenoside Rh2 was proposed as aparaptosis-like cell death inducer [42 58 59] Berberine and amodifiedChinese formulaYiGuan Jianmight induce cancercell anoikis [113 149 157] Pharicin A (from XiangchacaiIsodon amethystoides (Benth) H Hara) [123] and casticin(from Manjing Vitex rotundifolia Lf) [124] initiated mitoticcatastrophe in cancer Apart from the above-mentioned celldeath several other cell death pathways such as cornificationentosis netosis parthanatos and pyroptosis have also beendiscussed elsewhere [4 9ndash12] However to the best of ourknowledge none of the CMs is found to be involved in thesenovel pathways

In summary this paper reviewed 45 pure compoundsand extracts from CMs which can induce different cancercell death and the underlying mechanisms The overview ofthe flow chart is shown in Figure 4 Apparently cell death isnot only one mechanism of all these pure compounds andextracts for cancer therapy but also via other mechanismssuch as antiproliferation anti-invasion anti-angiogenesisand anti-inflammation [15] Since the natural sources of CMsare raw or processed materials focusing on low- or nontoxic


OO

OOHHO

OH

OHOHO

HO

Original medicinal herbs

Pure compounds

Whole extracts or fractions from herbs

O

O

OO

H

H

O

H

O

O

MeO

Apoptotic cell death

Autophagic cell death

Other cell deaths

Necroptotic cell death

N+

H3C

CH3

MeOCH3

Figure 4 The overview of the flow chart for this review paper The paper reviewed 45 pure compounds and extracts from CMs which caninduce different cancer cell death

dosages while all these CMs in this review are pure singlecompounds or extracts which induce cell death by cytotoxicdosage we should pay attention to careful explanation of theresults of all these CMs Basically CM practitioners do notuse pure compounds to treat diseases but CM practitionersbegin to integrate traditional use with results derived frommodern research including characteristics of CMs inducingcell death for cancer therapy in recent years For exampleberberine a main active compound of huanglian is notdirectly used in CM clinical practice but the various effects ofberberine in cancer cell models will bring some new insightinto clinical usage of huanglian when CM practitioners usehuanglian combined with other herbs to treat cancer Tanget al [158] Usually huanglian was used in low dosage 2ndash5 g to treat diseases while high dosage of huanglian at 15ndash30 g was also suggested for use in recent years because wefound that berberine could inhibit cancer cell migration inlow dosage while berberine could induce cell death in highdosage with safety Tang et al [15 111 158] For the highdosage of huanglian it needs further validation by clinicalstudyOn the other hand limited composite formula-inducedanticancer action via cell death pathway is known and onlyfew researches have been conducted from in vitro studymorestudies on composite Chinese medicine formula with goodquality control would be needed at themolecular and cellularlevel and clinical studies

4 Conclusions

This review showed that CMs treatment could inducemultiple cancer cell death pathways including apoptosisautophagy necrosis and other kinds of cell death in whichapoptosis is the most dominant type How to apply thesepreclinical researches to clinical application will be a keyissue in the future The summary about CMs inducing celldeath in this systematic review may offer insight into future

development of cancer drug discovery fromCMs and clinicalapplication of CMs in cancer treatment

Conflict of Interests

The authors declare there is no conflict of interests regardingthe publication of this paper

Acknowledgments

The study was financially supported by Grants fromthe research council of the University of Hong Kong(Project Codes 10401764 and 104002889) the OpenProject of Hubei Key Laboratory of Wudang Local ChineseMedicine Research Hubei University of Medicine (Grantno WDCM001) andThe Research Grant Committee (RGC)of Hong Kong (RGC General Research Fund Project Code10500362)

References

[1] A Jemal F Bray M M Center J Ferlay E Ward and DForman ldquoGlobal cancer statisticsrdquo CA A Cancer Journal forClinicians vol 61 no 2 pp 69ndash90 2011

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

[3] P G H Clarke ldquoDevelopmental cell death morphologicaldiversity and multiple mechanismsrdquo Anatomy and Embryologyvol 181 no 3 pp 195ndash213 1990

[4] R A Lockshin andZ Zakeri ldquoApoptosis autophagy andmorerdquoThe International Journal of Biochemistry and Cell Biology vol36 no 12 pp 2405ndash2419 2004

[5] A L Edinger and C BThompson ldquoDeath by design apoptosisnecrosis and autophagyrdquoCurrentOpinion inCell Biology vol 16no 6 pp 663ndash669 2004

[6] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implications


in tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972

[7] C W Wang and D J Klionsky ldquoThe molecular mechanism ofautophagyrdquoMolecular Medicine vol 9 no 3-4 pp 65ndash76 2003

[8] A Degterev Z Huang M Boyce et al ldquoChemical inhibitor ofnonapoptotic cell death with therapeutic potential for ischemicbrain injuryrdquo Nature Chemical Biology vol 1 no 2 pp 112ndash1192005

[9] L Galluzzi I Vitale J M Abrams et al ldquoMolecular def-initions of cell death subroutines recommendations of theNomenclature Committee on Cell Death 2012rdquo Cell Death andDifferentiation vol 19 no 1 pp 107ndash120 2012

[10] F Margottin-Goguet J Y Hsu A Loktev H Hsieh J DR Reimann and P K Jackson ldquoProphase destruction ofEmi1 by the SCF120573TrCPSlimb ubiquitin ligase activates theanaphase promoting complex to allow progression beyondprometaphaserdquo Developmental Cell vol 4 no 6 pp 813ndash8262003

[11] I B Roninson E V Broude and B D Chang ldquoIf not apoptosisthen what Treatment-induced senescence and mitotic catas-trophe in tumor cellsrdquo Drug Resistance Updates vol 4 no 5pp 303ndash313 2001

[12] C K Speirs M Hwang S Kim et al ldquoHarnessing the cell deathpathway for targeted cancer treatmentrdquoTheAmerican Journal ofCancer Research vol 1 no 1 pp 43ndash61 2011

[13] R V Ancuceanu and V Istudor ldquoPharmacologically active nat-ural compounds for lung cancerrdquo Alternative Medicine Reviewvol 9 no 4 pp 402ndash419 2004

[14] B Carmady and C A Smith ldquoUse of Chinese medicine bycancer patients a review of surveysrdquo Chinese Medicine vol 6article 22 2011

[15] Y Feng N Wang M Zhu H Li and S Tsao ldquoRecent progresson anticancer candidates in patents of herbal medicinal prod-uctsrdquo Recent Patents on Food Nutrition ampAgriculture vol 3 no1 pp 30ndash48 2011

[16] Y-H Lin and J-H Chiu ldquoUse of Chinese medicine amongpatients with liver cancer in Taiwanrdquo Journal of Alternative andComplementary Medicine vol 16 no 5 pp 527ndash528 2010

[17] C Y PuVM Lan C F Lan andHC Lang ldquoThedeterminantsof traditional Chinese medicine and acupuncture utilizationfor cancer patients with simultaneous conventional treatmentrdquoEuropean Journal of Cancer Care vol 17 no 4 pp 340ndash3492008

[18] L C Wong E Chan S Tay K M Lee and M BackldquoComplementary and alternative medicine practices amongAsian radiotherapy patientsrdquo Asia-Pacific Journal of ClinicalOncology vol 6 no 4 pp 357ndash363 2010

[19] M P Crespo-Ortiz and M Q Wei ldquoAntitumor activity ofartemisinin and its derivatives from a well-known antimalarialagent to a potential anticancer drugrdquo Journal of Biomedicine andBiotechnology vol 2012 Article ID 247597 18 pages 2012

[20] H Lai I Nakase E Lacoste N P Singh and T SasakildquoArtemisinin-transferrin conjugate retards growth of breasttumors in the ratrdquoAnticancer Research vol 29 no 10 pp 3807ndash3810 2009

[21] A E Mercer I M Copple J L Maggs P M OrsquoNeill and B KPark ldquoThe role of heme and the mitochondrion in the chemicaland molecular mechanisms of mammalian cell death inducedby the artemisinin antimalarialsrdquo The Journal of BiologicalChemistry vol 286 no 2 pp 987ndash996 2011

[22] Y Gong Y Li Y Lu et al ldquoBioactive tanshinones in Salviamiltiorrhiza inhibit the growth of prostate cancer cells in vitroand in micerdquo International Journal of Cancer vol 129 no 5 pp1042ndash1052 2011

[23] H L Tian T Yu N N Xu et al ldquoA novel compound modifiedfrom tanshinone inhibits tumor growth in vivo via activation ofthe intrinsic apoptotic pathwayrdquo Cancer Letters vol 297 no 1pp 18ndash30 2010

[24] S-H Won H-J Lee S-J Jeong et al ldquoTanshinone IIainduces mitochondria dependent apoptosis in prostate cancercells in association with an inhibition of phosphoinositide 3-kinaseAKT pathwayrdquo Biological and Pharmaceutical Bulletinvol 33 no 11 pp 1828ndash1834 2010

[25] I J Park M J Kim O J Park et al ldquoCryptotanshinonesensitizes DU145 prostate cancer cells to Fas(APO1CD95)-mediated apoptosis through Bcl-2 and MAPK regulationrdquoCancer Letters vol 298 no 1 pp 88ndash98 2010

[26] J Yu X Li S Tashiro S Onodera and T Ikejima ldquoBcl-2family proteins were involved in pseudolaric acid B-inducedautophagy in murine fibrosarcoma L929 cellsrdquo Journal ofPharmacological Sciences vol 107 no 3 pp 295ndash302 2008

[27] K-S Li X-F Gu P Li et al ldquoEffect of pseudolaric acid B ongastric cancer cells inhibition of proliferation and induction ofapoptosisrdquoTheWorld Journal of Gastroenterology vol 11 no 48pp 7555ndash7559 2005

[28] V K W Wong P Chiu S S M Chung et al ldquoPseudolaric acidB a novel microtubule-destabilizing agent that circumventsmultidrug resistance phenotype and exhibits antitumor activityin vivordquo Clinical Cancer Research vol 11 no 16 pp 6002ndash60112005

[29] R E deAngel SM Smith R D Glickman S N Perkins and SDHursting ldquoAntitumor effects of ursolic acid in amousemodelof postmenopausal breast cancerrdquoNutrition and Cancer vol 62no 8 pp 1074ndash1086 2010

[30] S W Shin S Y Kim and J Park ldquoAutophagy inhibitionenhances ursolic acid-induced apoptosis in PC3 cellsrdquo Biochim-ica et Biophysica Acta vol 1823 no 2 pp 451ndash457 2012

[31] K H Kim H S Seo H S Choi I H Choi Y C Shinand S-G Ko ldquoInduction of apoptotic cell death by ursolicacid through mitochondrial death pathway and extrinsic deathreceptor pathway inMDA-MB-231 cellsrdquoArchives of PharmacalResearch vol 34 no 8 pp 1363ndash1372 2011

[32] S H Kwon H Y Park J Y Kim I Y Jeong M K Lee andK I Seo ldquoApoptotic action of ursolic acid isolated from Cornifructus in RC-58ThSA4 primary human prostate cancercellsrdquo Bioorganic and Medicinal Chemistry Letters vol 20 no22 pp 6435ndash6438 2010

[33] A Pinon Y Limami L Micallef et al ldquoA novel form ofmelanoma apoptosis resistance melanogenesis up-regulationin apoptotic B16-F0 cells delays ursolic acid-triggered celldeathrdquo Experimental Cell Research vol 317 no 12 pp 1669ndash1676 2011

[34] N Wang W Pan M Zhu et al ldquoFangchinoline inducesautophagic cell death via p53sestrin2AMPK signalling inhuman hepatocellular carcinoma cellsrdquo The British Journal ofPharmacology vol 164 no 2 pp 731ndash742 2011

[35] S-L Yan C-Y Huang S-TWu andM-C Yin ldquoOleanolic acidand ursolic acid induce apoptosis in four human liver cancer celllinesrdquo Toxicology in Vitro vol 24 no 3 pp 842ndash848 2010

[36] N Mujumdar and A K Saluja ldquoAutophagy in pancreaticcancer an emerging mechanism of cell deathrdquo Autophagy vol6 no 7 pp 997ndash998 2010


[37] L Chen Q Liu Z Huang et al ldquoTripchlorolide induces celldeath in lung cancer cells by autophagyrdquo International Journalof Oncology vol 40 no 4 pp 1066ndash1070 2012

[38] K A Clawson D Borja-Cacho M B Antonoff A KSaluja and S M Vickers ldquoTriptolide and TRAIL combinationenhances apoptosis in cholangiocarcinomardquo Journal of SurgicalResearch vol 163 no 2 pp 244ndash249 2010

[39] Y Cheng F Qiu and T Ikejima ldquoMolecular mechanisms oforidonin-induced apoptosis and autophagy in murine fibrosar-coma L929 cellsrdquo Autophagy vol 5 no 3 pp 430ndash431 2009

[40] Y Cheng F Qiu Y-C Ye et al ldquoAutophagy inhibits reactiveoxygen species-mediated apoptosis via activating p38-nuclearfactor-kappa B survival pathways in oridonin-treated murinefibrosarcoma L929 cellsrdquo FEBS Journal vol 276 no 5 pp 1291ndash1306 2009

[41] Q Cui S Tashiro S Onodera M Minami and T IkejimaldquoAutophagy preceded apoptosis in oridonin-treated humanbreast cancer MCF-7 cellsrdquo Biological and PharmaceuticalBulletin vol 30 no 5 pp 859ndash864 2007

[42] C Li E Wang Y Cheng and J Bao ldquoOridonin an activediterpenoid targeting cell cycle arrest apoptotic and autophagicpathways for cancer therapeuticsrdquo International Journal ofBiochemistry and Cell Biology vol 43 no 5 pp 701ndash704 2011

[43] S Chen M Cooper M Jones et al ldquoCombined activity oforidonin and wogonin in advanced-stage ovarian cancer cellsrdquoCell Biology and Toxicology vol 27 no 2 pp 133ndash147 2011

[44] N Kang J Zhang F Qiu S Tashiro S Onodera and TIkejima ldquoInhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhanc-ing oxidative stress coincident with activation of both theintrinsic and extrinsic apoptotic pathwaysrdquo Cancer Letters vol294 no 2 pp 147ndash158 2010

[45] A Liu H Chen H Tong et al ldquoEmodin potentiates theantitumor effects of gemcitabine in pancreatic cancer cells viainhibition of nuclear factor-120581Brdquo Molecular Medicine Reportsvol 4 no 2 pp 221ndash227 2011

[46] B Liu P Yang Y Ye et al ldquoRole of ROS in the protective effectof silibinin on sodium nitroprusside-induced apoptosis in ratpheochromocytoma PC12 cellsrdquo Free Radical Research vol 45no 7 pp 835ndash847 2011

[47] J Liu Y Zhang J Qu et al ldquo120573-Elemene-induced autophagyprotects human gastric cancer cells fromundergoing apoptosisrdquoBMC Cancer vol 11 article 183 2011

[48] L Liu C Chen W Gong et al ldquoEpoxyeicosatrienoic acidsattenuate reactive oxygen species level mitochondrial dys-function caspase activation and apoptosis in carcinoma cellstreated with arsenic trioxiderdquo Journal of Pharmacology andExperimental Therapeutics vol 339 no 2 pp 451ndash463 2011

[49] X Peng Y Zhao X Liang et al ldquoAssessing the quality of RCTson the effect of 120573-elemene one ingredient of a Chinese herbagainstmalignant tumorsrdquoContemporary Clinical Trials vol 27no 1 pp 70ndash82 2006

[50] W Zhang ZWang and T Chen ldquoCurcumol induces apoptosisvia caspases-independent mitochondrial pathway in humanlung adenocarcinoma ASTC-a-1 cellsrdquo Medical Oncology vol28 no 1 pp 307ndash314 2011

[51] S H Cho K S Chung J H Choi D H Kim and K TLee ldquoCompound K a metabolite of ginseng saponin inducesapoptosis via caspase-8-dependent pathway in HL-60 humanleukemia cellsrdquo BMC Cancer vol 9 article 149 2009

[52] D Y Kim M W Park H D Yuan H J Lee S H Kim andS H Chung ldquoCompound K induces apoptosis via CAMK-IVAMPK pathways in HT-29 colon cancer cellsrdquo Journal ofAgricultural and Food Chemistry vol 57 no 22 pp 10573ndash10578 2009

[53] J I Lee Y W Ha T W Choi et al ldquoCellular uptake ofginsenosides in korean white ginseng and red ginseng andtheir apoptotic activities in human breast cancer cellsrdquo PlantaMedica vol 77 no 2 pp 133ndash140 2011

[54] S Park H-J Lee S-J Jeong et al ldquoInhibition of JAK1STAT3signaling mediates compound K-induced apoptosis in humanmultiple myeloma U266 cellsrdquo Food and Chemical Toxicologyvol 49 no 6 pp 1367ndash1372 2011

[55] G Song S Guo W Wang et al ldquoIntestinal metabolite com-pound K of ginseng saponin potently attenuates metastaticgrowth of hepatocellular carcinoma by augmenting apoptosisvia a bid-mediated mitochondrial pathwayrdquo Journal of Agricul-tural and Food Chemistry vol 58 no 24 pp 12753ndash12760 2010

[56] J Jian ZHu andYHuang ldquoEffect of ginsenoside Rg3 on Pim-3and Bad proteins in human pancreatic cancer cell line PANC-1rdquoChinese Journal of Cancer vol 28 no 5 pp 461ndash465 2009

[57] S M Kim S Y Lee D Y Yuk et al ldquoInhibition of NF-120581Bby ginsenoside Rg3 enhances the susceptibility of colon cancercells to docetaxelrdquo Archives of Pharmacal Research vol 32 no5 pp 755ndash765 2009

[58] B Li J Zhao C-Z Wang et al ldquoGinsenoside Rh2 inducesapoptosis andparaptosis-like cell death in colorectal cancer cellsthrough activation of p53rdquo Cancer Letters vol 301 no 2 pp185ndash192 2011

[59] W Li S Zhu J Li et al ldquoEGCG stimulates autophagy andreduces cytoplasmic HMGB1 levels in endotoxin-stimulatedmacrophagesrdquo Biochemical Pharmacology vol 81 no 9 pp1152ndash1163 2011

[60] S Choi J-Y Oh and S-J Kim ldquoGinsenoside Rh2 induces Bcl-2 family proteins-mediated apoptosis in vitro and in xenograftsin vivo modelsrdquo Journal of Cellular Biochemistry vol 112 no 1pp 330ndash340 2011

[61] J-H Kang K-H Song J-KWoo et al ldquoGinsenoside Rp1 fromPanax ginseng exhibits anti-cancer activity by down-regulationof the IGF-1RAkt pathway in breast cancer cellsrdquo Plant Foodsfor Human Nutrition vol 66 no 3 pp 298ndash305 2011

[62] A Kumar M Kumar T-Y Park et al ldquoMolecular mechanismsof ginsenoside Rp1-mediated growth arrest and apoptosisrdquoInternational Journal of Molecular Medicine vol 24 no 3 pp381ndash386 2009

[63] WH Lee J S Choi H Y Kim et al ldquoPotentiation of etoposide-induced apoptosis in HeLa cells by co-treatment with KG-135a quality-controlled standardized ginsenoside formulationrdquoCancer Letters vol 294 no 1 pp 74ndash81 2010

[64] R C Y Ong J Lei R K Y Lee et al ldquoPolyphyllin Dinduces mitochondrial fragmentation and acts directly on themitochondria to induce apoptosis in drug-resistant HepG2cellsrdquo Cancer Letters vol 261 no 2 pp 158ndash164 2008

[65] F M Siu D L Ma Y W Cheung et al ldquoProteomic andtranscriptomic study on the action of a cytotoxic saponin(Polyphyllin D) induction of endoplasmic reticulum stress andmitochondria-mediated apoptotic pathwaysrdquo Proteomics vol 8no 15 pp 3105ndash3117 2008

[66] H-Y Hsu J-S Yang K-W Lu et al ldquoAn experimental studyon the antileukemia effects of gypenosides in vitro and in vivordquoIntegrative Cancer Therapies vol 10 no 1 pp 101ndash112 2011


[67] J Gao W A Morgan A Sanchez-Medina and O CorcoranldquoThe ethanol extract of Scutellaria baicalensis and the activecompounds induce cell cycle arrest and apoptosis includingupregulation of p53 and Bax in human lung cancer cellsrdquoToxicology and Applied Pharmacology vol 254 no 3 pp 221ndash228 2011

[68] R-H Jiang W-C Su H-F Liu H-S Huang and J-IChao ldquoOpposite expression of securin and 120574-H2AX regulatesbaicalein-induced cancer cell deathrdquo Journal of Cellular Bio-chemistry vol 111 no 2 pp 274ndash283 2010

[69] H N Li F F NieW Liu et al ldquoApoptosis induction of oroxylinA in human cervical cancer HeLa cell line in vitro and in vivordquoToxicology vol 257 no 1-2 pp 80ndash85 2009

[70] W Liu R Mu F Nie et al ldquoMAC related mitochondrial path-way in oroxylin A induces apoptosis in human hepatocellularcarcinoma HepG2 cellsrdquo Cancer Letters vol 284 no 2 pp 198ndash207 2009

[71] G Polier J Ding B V Konkimalla et al ldquoWogonin and relatednatural flavones are inhibitors of CDK9 that induce apoptosis incancer cells by transcriptional suppression of Mcl-1rdquo Cell Deathand Disease vol 2 article e182 2011

[72] X Xu B Cai S Guan et al ldquoBaicalin induces humanmucoepi-dermoid carcinoma Mc3 cells apoptosis in vitro and in vivordquoInvestigational New Drugs vol 29 no 4 pp 637ndash645 2011

[73] X Zhang X Tang H Liu L Li Q Hou and J Gao ldquoAutophagyinduced by baicalin involves downregulation of CD147 inSMMC-7721 cells in vitrordquo Oncology Reports vol 27 no 4 pp1128ndash1134 2012

[74] L Yang X L Zheng H Sun et al ldquoCatalase suppression-mediated H2O2 accumulation in cancer cells by wogonin effec-tively blocks tumor necrosis factor-induced NF-120581B activationand sensitizes apoptosisrdquoCancer Science vol 102 no 4 pp 870ndash876 2011

[75] W-H Yang Y-C Fong C-Y Lee et al ldquoEpigallocatechin-3-gallate induces cell apoptosis of human chondrosarcoma cellsthrough apoptosis signal-regulating kinase 1 pathwayrdquo Journalof Cellular Biochemistry vol 112 no 6 pp 1601ndash1611 2011

[76] E J Choi and G-H Kim ldquoAnti-pro-apoptotic effects of hes-peretin against 712-dimetylbenz(a) anthracene-induced alter-ation in animalsrdquo Oncology Reports vol 25 no 2 pp 545ndash5502011

[77] R V Cluzan F Alliot S Ghabboun andM Pascot ldquoTreatmentof secondary lymphedema of the upper limb with CYCLO 3FORTrdquo Lymphology vol 29 no 1 pp 29ndash35 1996

[78] M Nazari A Ghorbani A Hekmat-Doost M Jeddi-Tehraniand H Zand ldquoInactivation of nuclear factor-120581B by citrusflavanone hesperidin contributes to apoptosis and chemo-sensitizing effect in Ramos cellsrdquo European Journal of Pharma-cology vol 650 no 2-3 pp 526ndash533 2011

[79] C S Lee Y J Kim M S Lee E S Han and S J Lee ldquo18120573-Glycyrrhetinic acid induces apoptotic cell death in SiHa cellsand exhibits a synergistic effect against antibiotic anti-cancerdrug toxicityrdquo Life Sciences vol 83 no 13-14 pp 481ndash489 2008

[80] B J Veldt B EHansenK Ikeda EVerheyH Suzuki and SWSchalm ldquoLong-term clinical outcome and effect of glycyrrhizinin 1093 chronic hepatitis C patients with non-response orrelapse to interferonrdquo Scandinavian Journal of Gastroenterologyvol 41 no 9 pp 1087ndash1094 2006

[81] M Yoshikawa M Toyohara S Ueda et al ldquoGlycyrrhizininhibits TNF-induced but not Fas-mediated apoptosis in thehuman hepatoblastoma line HepG2rdquo Biological amp Pharmaceu-tical Bulletin vol 22 no 9 pp 951ndash955 1999

[82] N Vidhya and S Niranjali Devaraj ldquoInduction of apoptosisby eugenol in human breast cancer cellsrdquo Indian Journal ofExperimental Biology vol 49 no 11 pp 871ndash878 2011

[83] L LAunMNAzmiH IbrahimKAwang andNHNagoorldquo11015840S-11015840-acetoxyeugenol acetate a novel phenylpropanoid fromAlpinia conchigera enhances the apoptotic effects of pacli-taxel in MCF-7 cells through NF-120581B inactivationrdquo Anti-CancerDrugs vol 22 no 5 pp 424ndash434 2011

[84] J Hoffmann H Junker A Schmieder et al ldquoEGCG downreg-ulates IL-1RI expression and suppresses IL-1-induced tumori-genic factors in human pancreatic adenocarcinoma cellsrdquo Bio-chemical Pharmacology vol 82 no 9 pp 1153ndash1162 2011

[85] Y C Lim and Y Y Cha ldquoEpigallocatechin-3-gallate inducesgrowth inhibition and apoptosis of human anaplastic thyroidcarcinoma cells through suppression of EGFRERK pathwayand cyclin B1CDK1 complexrdquo Journal of Surgical Oncology vol104 no 7 pp 776ndash780 2011

[86] H A Vu Y Beppu H T Chi et al ldquoGreen tea epigallocatechingallate exhibits anticancer effect in human pancreatic carci-noma cells via the inhibition of both focal adhesion kinase andinsulin-like growth factor-I receptorrdquo Journal of Biomedicineand Biotechnology vol 2010 Article ID 290516 8 pages 2010

[87] A A Alshatwi ldquoCatechin hydrate suppresses MCF-7 prolif-eration through TP53Caspase-mediated apoptosisrdquo Journal ofExperimental amp Clinical Cancer Research vol 29 no 1 article167 2010

[88] H S Oz and J L Ebersole ldquoGreen tea polyphenols mediatedapoptosis in intestinal epithelial cells by a FADD-dependentpathwayrdquo Journal of Cancer Therapy vol 1 no 3 pp 105ndash1132010

[89] S Tsukamoto K Hirotsu M Kumazoe et al ldquoGreen teapolyphenol EGCG induces lipid-raft clustering and apoptoticcell death by activating protein kinase C120575 and acid sphin-gomyelinase through a 67 kDa laminin receptor in multiplemyeloma cellsrdquoBiochemical Journal vol 443 no 2 pp 525ndash5342012

[90] L-YWu T de Luca TWatanabe DMMorre andD JMorreldquoMetabolite modulation of HeLa cell response to ENOX2inhibitors EGCG and phenoxodiolrdquo Biochimica et BiophysicaActa vol 1810 no 8 pp 784ndash789 2011

[91] Y C Chen F L Kung I L Tsai T H Chou I S Chenand J H Guh ldquoCryptocaryone a natural dihydrochalconeinduces apoptosis in human androgen independent prostatecancer cells by death receptor clustering in lipid raft and nonraftcompartmentsrdquoThe Journal of Urology vol 183 no 6 pp 2409ndash2418 2010

[92] R E Carroll R V Benya D K Turgeon et al ldquoPhase IIa clinicaltrial of curcumin for the prevention of colorectal neoplasiardquoCancer Prevention Research vol 4 no 3 pp 354ndash364 2011

[93] J H Kim S C Gupta B Park V R Yadav and B BAggarwal ldquoTurmeric (Curcuma longa) inhibits inflammatorynuclear factor (NF)-120581B and NF-120581B-regulated gene productsand induces death receptors leading to suppressed proliferationinduced chemosensitization and suppressed osteoclastogene-sisrdquoMolecularNutritionampFoodResearch vol 56 no 3 pp 454ndash465 2012

[94] Y-S Ma S-W Weng M-W Lin et al ldquoAntitumor effects ofemodin on LS1034 human colon cancer cells in vitro and invivo roles of apoptotic cell death and LS1034 tumor xenograftsmodelrdquo Food and Chemical Toxicology vol 50 no 5 pp 1271ndash1278 2012


[95] H Z Lee S L Hsu M C Liu and C H Wu ldquoEffectsand mechanisms of aloe-emodin on cell death in human lungsquamous cell carcinomardquo European Journal of Pharmacologyvol 431 no 3 pp 287ndash295 2001

[96] P Suboj S Babykutty P Srinivas and S Gopala ldquoAloe emodininduces G2M cell cycle arrest and apoptosis via activation ofcaspase-6 in human colon cancer cellsrdquo Pharmacology vol 89no 1-2 pp 91ndash98 2012

[97] H Kauntz S Bousserouel F Gosse and F Raul ldquoSilibinintriggers apoptotic signaling pathways and autophagic survivalresponse in human colon adenocarcinoma cells and theirderivedmetastatic cellsrdquoApoptosis vol 16 no 10 pp 1042ndash10532011

[98] R P Singh and R Agarwal ldquoProstate cancer prevention bysilibininrdquo Current Cancer Drug Targets vol 4 no 1 pp 1ndash112004

[99] R P Singh and R Agarwal ldquoProstate cancer chemopreventionby silibinin bench to bedsiderdquo Molecular Carcinogenesis vol45 no 6 pp 436ndash442 2006

[100] J Zeng Y Sun KWu et al ldquoChemopreventive and chemother-apeutic effects of intravesical silibinin against bladder cancer byacting onmitochondriardquoMolecular CancerTherapeutics vol 10no 1 pp 104ndash116 2011

[101] W Duan Q Li M Xia S Tashiro S Onodera and T IkejimaldquoSilibinin activated p53 and induced autophagic death in humanfibrosarcoma HT1080 cells via reactive oxygen species-p38 andc-Jun N-terminal kinase pathwaysrdquo Biological and Pharmaceu-tical Bulletin vol 34 no 1 pp 47ndash53 2011

[102] H B Huang D Chen S Li et al ldquoGambogic acid enhancesproteasome inhibitor-induced anticancer activityrdquo Cancer Let-ters vol 301 no 2 pp 221ndash228 2011

[103] S Kasibhatla K A Jessen S Maliartchouk et al ldquoA role fortransferrin receptor in triggering apoptosis when targeted withgambogic acidrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 34 pp 12095ndash121002005

[104] M K Pandey B Sung S A Kwang A B Kunnumakkara MM Chaturvedi and B B Aggarwal ldquoGambogic acid a novelligand for transferrin receptor potentiates TNF-induced apop-tosis through modulation of the nuclear factor-120581B signalingpathwayrdquo Blood vol 110 no 10 pp 3517ndash3525 2007

[105] RMin J Tong YWenjun et al ldquoGrowth inhibition and induc-tion of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by Shikoninwas partly through the inactivation ofNF-120581B pathwayrdquo Phytotherapy Research vol 22 no 3 pp 407ndash415 2008

[106] W Han J Xie L Li Z Liu and X Hu ldquoNecrostatin-1 revertsshikonin-induced necroptosis to apoptosisrdquo Apoptosis vol 14no 5 pp 674ndash686 2009

[107] W Han L Li S Qiu et al ldquoShikonin circumvents cancerdrug resistance by induction of a necroptotic deathrdquoMolecularCancer Therapeutics vol 6 no 5 pp 1641ndash1649 2007

[108] A Burgeiro C Gajate E H Dakir J A Villa-Pulgarın P JOliveira and F Mollinedo ldquoInvolvement of mitochondrial andB-RAFERK signaling pathways in berberine-induced apopto-sis in humanmelanoma cellsrdquoAnti-Cancer Drugs vol 22 no 6pp 507ndash518 2011

[109] K N Chidambara Murthy G K Jayaprakasha and B SPatil ldquoThe natural alkaloid berberine targets multiple pathwaysto induce cell death in cultured human colon cancer cellsrdquoEuropean Journal of Pharmacology vol 688 no 1ndash3 pp 14ndash212012

[110] P-L PengW-H Kuo H-C Tseng and F-P Chou ldquoSynergistictumor-killing effect of radiation and berberine combined treat-ment in lung cancer the contribution of autophagic cell deathrdquoInternational Journal of Radiation Oncology Biology Physicsvol 70 no 2 pp 529ndash542 2008

[111] N Wang Y Feng M Zhu et al ldquoBerberine induces autophagiccell death and mitochondrial apoptosis in liver cancer cells thecellular mechanismrdquo Journal of Cellular Biochemistry vol 111no 6 pp 1426ndash1436 2010

[112] S Letasiova S Jantova L Cipak and M MuckovaldquoBerberinemdashantiproliferative activity in vitro and induction ofapoptosisnecrosis of the U937 and B16 cellsrdquo Cancer Lettersvol 239 no 2 pp 254ndash262 2006

[113] J B Kim J H Yu E Ko et al ldquoThe alkaloid Berberineinhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell cycle arrestrdquoPhytomedicine vol 17 no 6 pp 436ndash440 2010

[114] H El Btaouri H Morjani Y Greffe E Charpentier andL Martiny ldquoRole of JNKATF-2 pathway in inhibition ofthrombospondin-1 (TSP-1) expression and apoptosis mediatedby doxorubicin and camptothecin in FTC-133 cellsrdquo Biochimicaet Biophysica Acta vol 1813 no 5 pp 695ndash703 2011

[115] Y Zhang C Wang H Wang K Wang Y Du and J ZhangldquoCombination of Tetrandrine with cisplatin enhances cyto-toxicity through growth suppression and apoptosis in ovariancancer in vitro and in vivordquo Cancer Letters vol 304 no 1 pp21ndash32 2011

[116] Z J Dai J Gao Z Z Ji et al ldquoMatrine induces apoptosis ingastric carcinoma cells via alteration of FasFasL and activationof caspase-3rdquo Journal of Ethnopharmacology vol 123 no 1 pp91ndash96 2009

[117] T Liu Y Song H Chen S Pan and X Sun ldquoMatrine inhibitsproliferation and induces apoptosis of pancreatic cancer cells invitro and in vivordquo Biological and Pharmaceutical Bulletin vol33 no 10 pp 1740ndash1745 2010

[118] Z Lin C-F Huang X-S Liu and J Jiang ldquoIn vitro anti-tumouractivities of quinolizidine alkaloids derived from Sophoraflavescens Aitrdquo Basic amp Clinical Pharmacology amp Toxicology vol108 no 5 pp 304ndash309 2011

[119] J-Q Zhang Y-M Li T Liu et al ldquoAntitumor effect ofmatrine in human hepatomaG2 cells by inducing apoptosis andautophagyrdquo The World Journal of Gastroenterology vol 16 no34 pp 4281ndash4290 2010

[120] S Zhang J Qi L Sun et al ldquoMatrine induces programmed celldeath and regulates expression of relevant genes based on PCRarray analysis inC6 glioma cellsrdquoMolecular Biology Reports vol36 no 4 pp 791ndash799 2009

[121] Q Ling X Xu X Wei et al ldquoOxymatrine induces humanpancreatic cancer PANC-1 cells apoptosis via regulating expres-sion of Bcl-2 and IAP families and releasing of cytochrome crdquoJournal of Experimental and Clinical Cancer Research vol 30no 1 article 66 2011

[122] S T Chou H Y Peng C T Chang et al ldquoZanthoxylumailanthoides Sieb and Zucc extract inhibits growth and inducescell death through G2M-phase arrest and activation of apop-totic signals in colo 205 human colon adenocarcinoma cellsrdquoAnticancer Research vol 31 no 5 pp 1667ndash1676 2011

[123] H Xu Y Huang Y Wu et al ldquoPharicin A a novel naturalent-kaurene diterpenoid induces mitotic arrest and mitoticcatastrophe of cancer cells by interfering with BubR1 functionrdquoCell Cycle vol 9 no 14 pp 2897ndash2907 2010


[124] J K Shen H P Du M Yang Y G Wang and J Jin ldquoCasticininduces leukemic cell death through apoptosis and mitoticcatastropherdquo Annals of Hematology vol 88 no 8 pp 743ndash7522009

[125] D Hu Q Liu H Cui H Wang D Han and H Xu ldquoEffectsof amino acids from selenium-rich silkworm pupas on humanhepatoma cellsrdquo Life Sciences vol 77 no 17 pp 2098ndash2110 2005

[126] B Tan J F Huang Q Wei H Zhang and R Z Ni ldquoAnti-hepatoma effect of arsenic trioxide on experimental liver cancerinduced by 2-acetamidofluorene in ratsrdquo World Journal ofGastroenterology vol 11 no 38 pp 5938ndash5943 2005

[127] E Calvino M C Estan G P Simon et al ldquoIncreased apoptoticefficacy of lonidamine plus arsenic trioxide combination inhuman leukemia cells Reactive oxygen species generation anddefensive protein kinase (MEKERK AktmTOR)modulationrdquoBiochemical Pharmacology vol 82 no 11 pp 1619ndash1629 2011

[128] C W Chien J H Yao S Y Chang P C Lee and T CLee ldquoEnhanced suppression of tumor growth by concomitanttreatment of human lung cancer cells with suberoylanilidehydroxamic acid and arsenic trioxiderdquo Toxicology and AppliedPharmacology vol 257 no 1 pp 59ndash66 2011

[129] H W Chiu Y A Chen S Y Ho and Y J Wang ldquoArsenic tri-oxide enhances the radiation sensitivity of androgen-dependentand -independent human prostate cancer cellsrdquo PLoS ONE vol7 no 2 Article ID e31579 2012

[130] R C Sun P G Board and A C Blackburn ldquoTargetingmetabolism with arsenic trioxide and dichloroacetate in breastcancer cellsrdquoMolecular Cancer vol 10 article 142 2011

[131] C Kuo T Wu L Chen et al ldquoCombination of arsenic trioxideand BCNU synergistically triggers redox-mediated autophagiccell death in human solid tumorsrdquo Free Radical Biology andMedicine vol 51 no 12 pp 2195ndash2209 2011

[132] K Cain ldquoChemical-induced apoptosis formation of the Apaf-1apoptosomerdquo Drug Metabolism Reviews vol 35 no 4 pp 337ndash363 2003

[133] M Castedo J-L Perfettini T Roumier K Andreau RMedema and G Kroemer ldquoCell death by mitotic catastrophe amolecular definitionrdquo Oncogene vol 23 no 16 pp 2825ndash28372004

[134] X Su X Wang F Zhang et al ldquoUrsolic acid inhibits prolifera-tion and induces apoptosis of cancer cells in vitro and in vivordquoJournal of Biomedicine and Biotechnology vol 2011 Article ID419343 8 pages 2011

[135] P Manikandan R S Murugan R V Priyadarsini G Vinothiniand S Nagini ldquoEugenol induces apoptosis and inhibits invasionand angiogenesis in a rat model of gastric carcinogenesisinduced by MNNGrdquo Life Sciences vol 86 no 25-26 pp 936ndash941 2010

[136] A T K Singh M Ghosh T M Forte R O Ryan and L IGordon ldquoCurcumin nanodisk-induced apoptosis in mantle celllymphomardquo Leukemia and Lymphoma vol 52 no 8 pp 1537ndash1543 2011

[137] F Ye L Xui J Yi W Zhang and D Y Zhang ldquoAnticanceractivity of Scutellaria baicalensis and its potential mechanismrdquoThe Journal of Alternative and Complementary Medicine vol 8no 5 pp 567ndash572 2002

[138] P S Patel N Joshee A M Rimando and P Parajuli ldquoAnti-cancer scopes and associated mechanisms of Scutellaria extractand flavonoid wogoninrdquo Current Cancer Therapy Reviews vol9 no 1 pp 34ndash42 2013

[139] S Ikemoto K Sugimura N Yoshida et al ldquoAntitumor effectsof Scutellariae radix and its components baicalein baicalin and

wogonin on bladder cancer cell linesrdquoUrology vol 55 no 6 pp951ndash955 2000

[140] B Y Khoo S L Chua and P Balaram ldquoApoptotic effects ofchrysin in human cancer cell linesrdquo International Journal ofMolecular Sciences vol 11 no 5 pp 2188ndash2199 2010

[141] Y-X Wu and X Fang ldquoApigenin chrysin and luteolin selec-tively inhibit chymotrypsin-like and trypsin-like proteasomecatalytic activities in tumor cellsrdquo Planta Medica vol 76 no 2pp 128ndash132 2010

[142] R Kachadourian H M Leitner and B J Day ldquoSelectedflavonoids potentiate the toxicity of cisplatin in human lungadenocarcinoma cells a role for glutathione depletionrdquo Inter-national Journal of Oncology vol 31 no 1 pp 161ndash168 2007

[143] H M Brechbuhl R Kachadourian E Min D Chan and BJ Day ldquoChrysin enhances doxorubicin-induced cytotoxicity inhuman lung epithelial cancer cell lines the role of glutathionerdquoToxicology and Applied Pharmacology vol 258 no 1 pp 1ndash92012

[144] R Kachadourian and B J Day ldquoFlavonoid-induced glutathionedepletion potential implications for cancer treatmentrdquo FreeRadical Biology and Medicine vol 41 no 1 pp 65ndash76 2006

[145] LGalluzzi andGKroemer ldquoNecroptosis a specialized pathwayof programmednecrosisrdquoCell vol 135 no 7 pp 1161ndash1163 2008

[146] Z Ma K Otsuyama S Liu et al ldquoBaicalein a component ofScutellaria radix fromHuang-Lian-Jie-Du-Tang (HLJDT) leadsto suppression of proliferation and induction of apoptosis inhuman myeloma cellsrdquo Blood vol 105 no 8 pp 3312ndash33182005

[147] Y L Hsu P L Kuo T F Tzeng et al ldquoHuang-lian-jie-du-tanga traditional Chinese medicine prescription induces cell-cyclearrest and apoptosis in human liver cancer cells in vitro and invivordquo Journal of Gastroenterology and Hepatology vol 23 no 7part 2 pp e290ndashe299 2008

[148] M B Antonoff R Chugh S J Skube et al ldquoRole of Hsp-70in triptolide-mediated cell death of neuroblastomardquo Journal ofSurgical Research vol 163 no 1 pp 72ndash78 2010

[149] M J Kim T H Lee S H Kim Y Choi J Heo and Y KimldquoTriptolide inactivates Akt and induces caspase-dependentdeath in cervical cancer cells via the mitochondrial pathwayrdquoInternational Journal of Oncology vol 37 no 5 pp 1177ndash11852010

[150] L Lu J Kanwar S Schmitt et al ldquoInhibition of tumor cellularproteasome activity by triptolide extracted from the Chinesemedicinal plant ldquothunder god vinerdquordquo Anticancer Research vol31 no 1 pp 1ndash10 2011

[151] F Zhao Y Chen L Zeng et al ldquoEffects of triptolide on RIZ1expression proliferation and apoptosis in multiple myelomaU266 cellsrdquo Acta Pharmacologica Sinica vol 31 no 6 pp 733ndash740 2010

[152] G S Zhou ZHuHT Fang et al ldquoBiologic activity of triptolidein t(821) acute myeloid leukemia cellsrdquo Leukemia Research vol35 no 2 pp 214ndash218 2011

[153] J M Tarr N Ding K Kaul A Antonell L A Perez-Juradoand R Chibber ldquoCellular crosstalk between TNF-120572 NADPHoxidase PKC1205732 and C2GNT in human leukocytesrdquo CellularSignalling vol 24 no 4 pp 873ndash878 2012

[154] N Mizushima A Yamamoto M Matsui T Yoshimori and YOhsumi ldquoIn vivo analysis of autophagy in response to nutri-ent starvation using transgenic mice expressing a fluorescentautophagosome markerrdquo Molecular Biology of the Cell vol 15no 3 pp 1101ndash1111 2004


[155] S Sperandio K Poksay I de Belle et al ldquoParaptosis mediationby MAP kinases and inhibition by AIP-1Alixrdquo Cell Death andDifferentiation vol 11 no 10 pp 1066ndash1075 2004

[156] YWang X Li LWang et al ldquoAn alternative formof paraptosis-like cell death triggered by TAJTROY and enhanced byPDCD5 overexpressionrdquo Journal of Cell Science vol 117 part 8pp 1525ndash1532 2004

[157] B Hu H An K Shen et al ldquoModified Yi Guan Jian aChinese herbal formula induces anoikis in Bel-7402 humanhepatocarcinoma cells in vitrordquo Oncology Reports vol 26 no6 pp 1465ndash1470 2011

[158] J Tang Y Feng S Tsao N Wang R Curtain and Y WangldquoBerberine andCoptidis rhizoma as novel antineoplastic agentsa review of traditional use and biomedical investigationsrdquoJournal of Ethnopharmacology vol 126 no 1 pp 5ndash17 2009

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


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


fusion involve the degradation of the components in cancercells through the lysosomal machinery [7] Type III cell deathis a necrotic process whose typical characteristics of necrosisinclude disruption of plasma membrane and induction ofinflammation that have been conventionally regarded as anaccidental uncontrolled cell death However recent studiesfound that necrosis could be under control as it sharedthe same stimuli (cytokines pathogens ischemia heat andirradiation) signaling pathways (death receptors kinase cas-cades and mitochondrial) and protective mechanisms (Bcl-2Bcl-x heat shock protein) as apoptosis [5 8] Besides thesethree types of cell death several other cell death pathwayshave been elucidated [4 9ndash12] Since these distinct cell deathshave different subroutines the Nomenclature Committee onCell Death (NCCD) has proposed a set of recommendationsto define cell deaths based on the biochemical and functionalcondensation in 2012 [9]

Since many of the clinical anticancer drugs are originallyfrom natural sources such as vinca alkaloids and taxanes upto date some studies have focused on the herbal medicinalproducts especially Chinese medicines (CMs includingplants animals and minerals) [13ndash18] Natural productsare important sources of anticancer lead molecules Manysuccessful anticancer drugs come from natural productsMore are still under clinical trialsThe aim is to develop novelanticancer drugs derived from natural products especiallyfrom CMs More critical systematic studies on cellular andmolecular therapeutic principle of anticancer natural prod-ucts from CMs in cancer cell deaths need to be conducted

In this review we retrieved the relevant publications fromPubMed and other databases to summarize the actions ofCMs involved in inducing cancer cell death in vitro andin vivo Besides clinical applications other novel cell deathpathways and the relevance of CMs in these fields are alsodiscussed here

2 CMs Induce CancerCell Death and Their UnderlyingMechanisms

21 CMs Induce Apoptotic Death in Human Cancer CellsBoth intrinsic and extrinsic pathways involve activation ofapoptosis by CMs in human cancer cells The CM-initiatedapoptotic cell death is mainly dependent on the activation ofcaspase cascade There are two types of apoptotic caspasesinitiator (apical) caspases and effector (executioner) caspasesInitiator caspases (eg CASP2 CASP8 CASP9 and CASP10)cleave inactive proforms of effector caspases thereby activat-ing them Initially caspases are cysteine-aspartic proteases orcysteine-dependent aspartate-directed proteases in inactiveformsThey are cleaved by interacting special molecules suchas Apaf-1 (apoptotic protease-activating factor-1) FasCD95or tumor necrosis factor 120572 (TNF120572) when apoptosis is inducedin cells [9 132] Extrinsic apoptosis depends on caspaseactivation while intrinsic apoptosis is either in caspase-dependent or -independentmanner [9 133] CMs can activatecancer cell death extrinsically intrinsically or both thereforethe mechanisms of CMs inducing cancer apoptotic cell death

have been more diversified Table 1 summarizes the generalinformation ofCMs inducing apoptotic cell deathThe typicalexamples are in Table 1 and Figure 1

211 CMs Induce Apoptosis Intrinsically CMs-inducedintrinsic apoptosis mainly requires the activation of caspasesCMs can also induce apoptotic cell death by caspase-independent manner because some types of cancer cellscan ablate the expression of caspases In addition even incaspase-proficient cancer cells CMs treatment can activateall types of intrinsic apoptosis eventually leading to potentcancer cell death

Ursolic acid (UA) is an active ingredient in several CMssuch as Oldenlandia diffusa (Willd) Roxb (Chinese nameBaihuasheshecao) Ligustrum lucidum WTAiton (Chinesename Nuzhen) and Eriobotrya japonica (Thunb) Lindl(Chinese name Pipa) Previous studies showed that UAcould induce cancer cell death by enabling the caspase-dependent pathway It was reported that UA activatedcaspase-3 and caspase-9 in human prostate cancer cellsRC-58ThSA4 [32] UA binding with oleanolic acid couldelevate the caspase-3 activity in human liver cancer cellsHuh7 HepG2 Hep3B and HA22T [35] Its antitumoreffect was also observed in xenograft model The resultsof positron-emission tomography-computed tomography(PET-CT) imaging indicated that proliferation of tumor cellsdeclined after UA treatment in vivo [34 134] Generally themechanism of CMs to cause intrinsic cell death in cancer iscaspase-dependent CMs induced the release of cytochromec from mitochondria [23] which facilitated the activationof apoptotic protease-activating factor-1 (Apaf-1) and formsApaf-1 apoptosome that bound to caspase-9 through CARD-CARD (caspase recruitment domain) interactions to forma holoenzyme complex [135 136] The complex cleavedcaspase-3 to produce a caspase cascade resulting in celldeath [94 136]Themechanisms of some representative CMsinducing cancer intrinsic cell death are illustrated in Figure 1

Apart from caspase-dependent cell death CMs couldinitiate apoptosis in both caspase-dependent and caspase-independent manners The main biochemical pathway ofcaspase-independent cell apoptosis was elucidated as theresults of release of mitochondrial intermembrane space(IMS) proteins and inhibition of respiratory chain In thiscontext apoptosis-inducing factor (AIF) and endonucleaseG (Endo G) relocated to the nucleus and mediate large-scale DNA fragmentation The serine protease a high tem-perature requirement protein A2 (HTRA2) cleaved manycellular substrates including cytoskeletal proteins as well[9] Gypenosides (Gyp) derived from Gynostemma penta-phyllum (Thunb) Makino (Chinese name Jiaogulan) couldsuppress the growth of WEHI-3 cells in vitro and in vivothrough caspase-dependent and -independent apoptosisGyp inhibited Bcl-2 increased Bax and induced the releaseof cytochrome c and depolarization of mitochondrial mem-brane potential (Δ120595) and stimulated the activities of caspase-3 and caspase-8 suggesting that Gyp triggered caspase-dependent cell death Gyp also induced the generationof ROS and stimulated the release of AIF and Endo G







Ursolic acid















inactivation)[83]








Table 1 Continued



















Extrinsic pathway

FasL

FADD

Pro

Caspase-810

Pro Caspase-3

Caspase-3

Caspases 6 7

Mitochondria

BaxBak

Bcl-2Bcl-xL

Apaf-1

cFLIPs cIAPs

Nucleus

DNA fragmentation

IAPs

IMS proteinsendo G

AIF

SmacDIABLO

CytC

TRAIL-R1

FasCD95APO-1



PARP

P53

DR45

DR45

Apoptosis




AE

ATO

CU

REM

O M

ATCRP

CAM BER

CUR

ES SRA ATO


Caspase-810

TNF-120572

TRAIL-R2

CRP

Caspase-9





ES ATO

AE BER BL EL CAM

EMO GA GY HES

OR ORA PD TET

OX TH WO

CAT CUR

HSP27

BER GY SIL AE ES

SHITET AE B

ER EMO

GA OX A

TO


AE

AR BAI GC TET W

O


SIL CAM MAT ATO

AE EL WOGC TH EL ES






ORIL-3

JNK

Atg3Ulk1

FIP200

PI3K

Mitochondria

mTOR

Nucleus

Akt

Autophagy

Bif

IL-3R

IKK

Bid

Apoptosis

Prosurvival genes

IKK


ATO BER UA

TRI ATOOR

FA

Bcl-2Bcl-xL

TNF-120572


DR45TRAIL-R2

ROS

SIL

PAB

Caspases

UVRAG

SIL

AMPK



3 Discussion





FasL

FADD

TRADD

JNK

Nucleus

DNA

PRAP

Necrosisnecroptosis

FADD

RIP3

RIP1


Necrostatins

AIF

TNF-120572

TRAIL-R1 DR45

DR45TRAIL-R2

FasCD95APO-1

Ca2+ ROS







OO

OOHHO

OH

OHOHO

HO


Pure compounds


O

O

OO

H

H

O

H

O

O

MeO



Other cell deaths


N+

H3C

CH3

MeOCH3



4 Conclusions





Acknowledgments


References












































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















Ursolic acid















inactivation)[83]








Table 1 Continued



















Extrinsic pathway

FasL

FADD

Pro

Caspase-810

Pro Caspase-3

Caspase-3

Caspases 6 7

Mitochondria

BaxBak

Bcl-2Bcl-xL

Apaf-1

cFLIPs cIAPs

Nucleus

DNA fragmentation

IAPs

IMS proteinsendo G

AIF

SmacDIABLO

CytC

TRAIL-R1

FasCD95APO-1



PARP

P53

DR45

DR45

Apoptosis




AE

ATO

CU

REM

O M

ATCRP

CAM BER

CUR

ES SRA ATO


Caspase-810

TNF-120572

TRAIL-R2

CRP

Caspase-9





ES ATO

AE BER BL EL CAM

EMO GA GY HES

OR ORA PD TET

OX TH WO

CAT CUR

HSP27

BER GY SIL AE ES

SHITET AE B

ER EMO

GA OX A

TO


AE

AR BAI GC TET W

O


SIL CAM MAT ATO

AE EL WOGC TH EL ES






ORIL-3

JNK

Atg3Ulk1

FIP200

PI3K

Mitochondria

mTOR

Nucleus

Akt

Autophagy

Bif

IL-3R

IKK

Bid

Apoptosis

Prosurvival genes

IKK


ATO BER UA

TRI ATOOR

FA

Bcl-2Bcl-xL

TNF-120572


DR45TRAIL-R2

ROS

SIL

PAB

Caspases

UVRAG

SIL

AMPK



3 Discussion





FasL

FADD

TRADD

JNK

Nucleus

DNA

PRAP

Necrosisnecroptosis

FADD

RIP3

RIP1


Necrostatins

AIF

TNF-120572

TRAIL-R1 DR45

DR45TRAIL-R2

FasCD95APO-1

Ca2+ ROS







OO

OOHHO

OH

OHOHO

HO


Pure compounds


O

O

OO

H

H

O

H

O

O

MeO



Other cell deaths


N+

H3C

CH3

MeOCH3



4 Conclusions





Acknowledgments


References












































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 1 Continued



















Extrinsic pathway

FasL

FADD

Pro

Caspase-810

Pro Caspase-3

Caspase-3

Caspases 6 7

Mitochondria

BaxBak

Bcl-2Bcl-xL

Apaf-1

cFLIPs cIAPs

Nucleus

DNA fragmentation

IAPs

IMS proteinsendo G

AIF

SmacDIABLO

CytC

TRAIL-R1

FasCD95APO-1



PARP

P53

DR45

DR45

Apoptosis




AE

ATO

CU

REM

O M

ATCRP

CAM BER

CUR

ES SRA ATO


Caspase-810

TNF-120572

TRAIL-R2

CRP

Caspase-9





ES ATO

AE BER BL EL CAM

EMO GA GY HES

OR ORA PD TET

OX TH WO

CAT CUR

HSP27

BER GY SIL AE ES

SHITET AE B

ER EMO

GA OX A

TO


AE

AR BAI GC TET W

O


SIL CAM MAT ATO

AE EL WOGC TH EL ES






ORIL-3

JNK

Atg3Ulk1

FIP200

PI3K

Mitochondria

mTOR

Nucleus

Akt

Autophagy

Bif

IL-3R

IKK

Bid

Apoptosis

Prosurvival genes

IKK


ATO BER UA

TRI ATOOR

FA

Bcl-2Bcl-xL

TNF-120572


DR45TRAIL-R2

ROS

SIL

PAB

Caspases

UVRAG

SIL

AMPK



3 Discussion





FasL

FADD

TRADD

JNK

Nucleus

DNA

PRAP

Necrosisnecroptosis

FADD

RIP3

RIP1


Necrostatins

AIF

TNF-120572

TRAIL-R1 DR45

DR45TRAIL-R2

FasCD95APO-1

Ca2+ ROS







OO

OOHHO

OH

OHOHO

HO


Pure compounds


O

O

OO

H

H

O

H

O

O

MeO



Other cell deaths


N+

H3C

CH3

MeOCH3



4 Conclusions





Acknowledgments


References












































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Extrinsic pathway

FasL

FADD

Pro

Caspase-810

Pro Caspase-3

Caspase-3

Caspases 6 7

Mitochondria

BaxBak

Bcl-2Bcl-xL

Apaf-1

cFLIPs cIAPs

Nucleus

DNA fragmentation

IAPs

IMS proteinsendo G

AIF

SmacDIABLO

CytC

TRAIL-R1

FasCD95APO-1



PARP

P53

DR45

DR45

Apoptosis




AE

ATO

CU

REM

O M

ATCRP

CAM BER

CUR

ES SRA ATO


Caspase-810

TNF-120572

TRAIL-R2

CRP

Caspase-9





ES ATO

AE BER BL EL CAM

EMO GA GY HES

OR ORA PD TET

OX TH WO

CAT CUR

HSP27

BER GY SIL AE ES

SHITET AE B

ER EMO

GA OX A

TO


AE

AR BAI GC TET W

O


SIL CAM MAT ATO

AE EL WOGC TH EL ES






ORIL-3

JNK

Atg3Ulk1

FIP200

PI3K

Mitochondria

mTOR

Nucleus

Akt

Autophagy

Bif

IL-3R

IKK

Bid

Apoptosis

Prosurvival genes

IKK


ATO BER UA

TRI ATOOR

FA

Bcl-2Bcl-xL

TNF-120572


DR45TRAIL-R2

ROS

SIL

PAB

Caspases

UVRAG

SIL

AMPK



3 Discussion





FasL

FADD

TRADD

JNK

Nucleus

DNA

PRAP

Necrosisnecroptosis

FADD

RIP3

RIP1


Necrostatins

AIF

TNF-120572

TRAIL-R1 DR45

DR45TRAIL-R2

FasCD95APO-1

Ca2+ ROS







OO

OOHHO

OH

OHOHO

HO


Pure compounds


O

O

OO

H

H

O

H

O

O

MeO



Other cell deaths


N+

H3C

CH3

MeOCH3



4 Conclusions





Acknowledgments


References












































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ORIL-3

JNK

Atg3Ulk1

FIP200

PI3K

Mitochondria

mTOR

Nucleus

Akt

Autophagy

Bif

IL-3R

IKK

Bid

Apoptosis

Prosurvival genes

IKK


ATO BER UA

TRI ATOOR

FA

Bcl-2Bcl-xL

TNF-120572


DR45TRAIL-R2

ROS

SIL

PAB

Caspases

UVRAG

SIL

AMPK



3 Discussion





FasL

FADD

TRADD

JNK

Nucleus

DNA

PRAP

Necrosisnecroptosis

FADD

RIP3

RIP1


Necrostatins

AIF

TNF-120572

TRAIL-R1 DR45

DR45TRAIL-R2

FasCD95APO-1

Ca2+ ROS







OO

OOHHO

OH

OHOHO

HO


Pure compounds


O

O

OO

H

H

O

H

O

O

MeO



Other cell deaths


N+

H3C

CH3

MeOCH3



4 Conclusions





Acknowledgments


References












































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















FasL

FADD

TRADD

JNK

Nucleus

DNA

PRAP

Necrosisnecroptosis

FADD

RIP3

RIP1


Necrostatins

AIF

TNF-120572

TRAIL-R1 DR45

DR45TRAIL-R2

FasCD95APO-1

Ca2+ ROS







OO

OOHHO

OH

OHOHO

HO


Pure compounds


O

O

OO

H

H

O

H

O

O

MeO



Other cell deaths


N+

H3C

CH3

MeOCH3



4 Conclusions





Acknowledgments


References












































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OO

OOHHO

OH

OHOHO

HO


Pure compounds


O

O

OO

H

H

O

H

O

O

MeO



Other cell deaths


N+

H3C

CH3

MeOCH3



4 Conclusions





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

























































































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
















Documents

Review Article Chinese Medicines Induce Cell Death: The ...downloads.hindawi.com/journals/bmri/2014/530342.pdf · Review Article Chinese Medicines Induce Cell Death: The Molecular