Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature

Published OnlineFirst August 26, 2014; DOI: 10.1158/1940-6207.CAPR-14-0136

Cancer Prevention Review Research

Faya M. Millimouno1,2,3, Jia Dong1, Liu Yang2, Jiang Li2, and Xiaomeng Li1

Abstract Although the incidences are increasing day after day, scientists and researchers taken individually or by research group are trying to fight against cancer by several ways and also by different approaches and techniques. Sesquiterpenes, flavonoids, alkaloids, diterpenoids, and polyphenolic represent a large and diverse group of naturally occurring compounds found in a variety of fruits, vegetables, and medicinal plants with various anticancer properties. In this review, our aim is to give our perspective on the current status of the natural compounds belonging to these groups and discuss their natural sources, their anticancer activity, their molecular targets, and their mechanism of actions with specific emphasis on apoptosis pathways, which may help the further design and conduct of preclinical and clinical trials. Unlike pharmaceutical drugs, the selected natural compounds induce apoptosis by targeting multiple cellular signaling pathways including transcription factors, growth factors, tumor cell survival factors, inflammatory cytokines, protein kinases, and angiogenesis that are frequently deregulated in cancers and suggest that their simultaneous targeting by these compounds could result in efficacious and selective killing of cancer cells. This review suggests that they provide a novel opportunity for treatment of cancer, but clinical trials are still required to further validate them in cancer chemotherapy. Cancer Prev Res; 7(11); 1081–107. 2014 AACR.

Introduction such as, antiapoptotic proteins, growth factors, growth Cancer is a major public health problem and the second factor receptors, transcription factors, and tumor suppres- leading cause of mortality around the world, mainly Europe sors, which constituted the target for cancer treatment. and the United States with an incident rate of about 2.6 Prevailing treatment options have limited therapeutic suc- million cases per year (1, 2). It is characterized by unsched- cess in cancer in the past decade. The concept of chemo- uled and uncontrolled cellular proliferation in the spectrum prevention is gaining increasing attention because it is a of cell. Cancer incidence in developing countries has been cost-effective alternative for cancer treatment (5). Cancer prevailed by tumor types that are related to viral, genetic chemoprevention by natural compounds, especially phy- mutations, and bacterial contamination (3). Cancer has a tochemicals, minerals, and vitamins, in a number of studies in vitro in vivo high incidence and a long period of latency on its devel- under both and conditions has shown opment and in the progression of the sickness. There are promising results against various malignancies (6). numerous risk factors known concerning the development In the development of bioactive chemical, natural pro- of cancer including age, geographic area, and race (4). ducts have a rich and long history. Herbal medicines, as an However, cancer is mostly a preventable disease. important novel source with a wide range of pharmaceutical Regardless of whether a cancer speciﬁcally results from a potential, are being used to treat human ailments including genetic mutation and viral or bacterial contamination, the almost all kinds of cancer (7). recent extensive research indicated that most cancers are The involvement of multiple factors underlying develop- caused by dysfunction of many genes coding for proteins mental stages of cancer at epigenetic, genetic, cellular, and molecular levels is opening up enormous opportunities to interrupt and reverse the initiation and progression of the 1The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics disease and provide scientists and researchers with numer- and Cytology, Northeast Normal University, Changchun, China. 2Dental ous targets to arrest by physiologic and pharmacologic Hospital, Jilin University, Changchun, China. 3Higher Institute of Science and Veterinary Medicine of Dalaba, Dalaba, Guinea. mechanisms to delay the development of cancer. The aim of this review is to summarize recent researches on twelve F.M. Millimouno and J. Dong contributed equally to this work. (12) natural compounds, such as ﬂavonoids (honokiol, Corresponding Authors: Xiaomeng Li, School of Life Sciences, Northeast magnolol, jaceosidin, and casticin), sesquiterpenes (parthe- Normal University, Renmin Street 5268, Changchun, China. Phone: 86- 431-85099285; Fax: 86-431-85099285; E-mail: [email protected]; nolide, costunolide, isoalantolactone, and alantolactone), and Jiang Li, Jilin University, Changchun 130021, China. Phone: 86- alkaloid (evodiamine), diterpenoids (oridonin and pseu- 186-86531019; Fax: 86-431-85579335; E-mail: [email protected] dolaric acid B), and polyphenolic (wedelolactone) focusing doi: 10.1158/1940-6207.CAPR-14-0136 on anticancer activity. The literature was screened from 2014 American Association for Cancer Research. various sites including PubMed, Scopus, and Elsevier

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Millimouno et al.

Science Direct Journal. Access to the Elsevier Science Direct effects, including antifungal, antihelmintic, antimicrobial, Journal was made possible through library of Northeast anti-inflammatory, antitrypanosomal, and antiproliferative Normal University, Changchun, China. We propose that effects on various cancer types as described in Tables 1 the development of natural compounds into new antican- and 2. cer agents has a bright future despite some difficulties. Role of Natural Compounds in Cancer Prevention Natural Sources and Biologic Activities of Plants provide an extensive reservoir of natural pro- Anticancer Chemopreventive Agents ducts, demonstrating important structural diversity, and Natural products are important and valuable resources offer a wide variety of novel and exciting chemical entities for drug development. Extensive researches have been car- and have a long history of use in the treatment of several ried out on the phytochemicals for their health-promoting illnesses. The significance of natural products in health potential. They have been found in fruits, vegetables, nuts, care is supported by a report that 80% of the global seeds, herbs, spices, stems, flowers, and tea. The phyto- population still relies on plant-derived medicines to constituent from these plants was extracted by several addresstheirhealthcareneeds(8).Itisalsoreported techniques, mainly high-performance liquid chromatogra- that 50% of all drugs in clinical use are natural products, phy, micellar electrokinetic chromatography, microemul- or their derivatives, or their analogs (9), and 74% of the sion electrokinetic chromatography, and their structures most important drugs consist of plant-derived active were elucidated on the basis of nuclear magnetic resonance ingredients (10). There are more than 3,000 plant species analysis (Fig. 1). that have been reported to be used in the treatment of The selected natural compounds among diterpenoids, cancer in modern medicine (11–14). sesquiterpenes, flavonoids, alkaloids, and polyphenolic There is a continued interest in the investigation of have been reported for their wide spectrum of biologic extracts of microorganisms, terrestrial plants, and marine

Sesquiterpenes compounds Flavonoids compounds Diterpenoids compounds

H3C OH CH OH 2

O OH

O HO O OH H C CH OH O 3 3 OH PARTHINOLIDE HONOKIOL CH3 ORIDONIN Tanacetum parthenium Magnolia grandiflora Isodon rubescens

H O HO O O H3C COOCH3 O O H H OH O COSTUNOLIDE MAGNOLOL PSEUDOLARIC ACID B Inula helenium Magnolia officinalis Pseudolarix kaempferi Polyphenolic compound CH H 3 OH OH O O HO O OH O OH O

H H O CH CH 2 O 2 OH O O O ISOALANTOLACTONE JACEOSIDIN WEDELOLACTONE Inula helenium L. Artemisia princeps Wedelia chinensis Alkaloid compound OH CH3 H OCH3 O O O H3CO O H N

H CO OCH3 H H 3 O N N CH CH2 OH 2 H ALANTOLACTONE CASTICIN Inula racemosa Vitex rotundifolia EVODIAMINE Evodia rutaecarpa

Figure 1. Chemical structure of the promising natural compounds and major natural sources.

1082 Cancer Prev Res; 7(11) November 2014 Cancer Prevention Research

Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds

Compound Natural source Mode of action Type of cancers Synergistic Major targets Flavonoids cancerpreventionresearch.aacrjournals.org

Honokiol Magnolia officinalis, Magnolia Antioxidant, antiproliferation Glioblastoma, melanoma, Fluconazole, CDK1?, Bcl-2#, Bax", cyclin D1#, Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 grandiflora, Magnolia spp. (cell-cycle arrest, apoptosis), gastric, leukemia, skin, Epigallocatechi n pAKT#, g-secretase activity#, anti-inflammation, colon, breast, ovarian, gallate (EGCG), TNFa g-secretase complex proteins#, antiangiogenesis, pancreatic, hepatocellular, PPAR-g?, COX-2?, NF-kB?, antiautophagy, colorectal, lung, prostate, EGFR/P13K/AKt#; JunB # and immunomodulation, human renal mesangial, JunD# caspase-8", caspase-9", anticancer, gastrointestinal head and neck squamous caspase-3", PARP", p53", disorders, cough, anxiety, carcinoma CD31 staining#,LH", p38?, NF- and allergies kB?, Bcl-XL#, Bad", cyclin E#, (Cdk2 and Cdk4)#,Cdk", p21 and p27", NF-kB#, Bcl-2#, Mcl- 1#, surcivin#, VEGF#, STAT3?, Cancer Research. HG-induced IL1b?, IL18?, TNFa?, -PGE2?,NO?, and TGFb1?, MCP-1?, MIP-1a?, EGFR targeting TKI?, Akt? on September 28, 2021. © 2014American Association for erlotinib?, EGFR signaling?, MAPK?, cyclin D1?

antidepressant, antioxidant, epitheloid carcinoma, A#, CDK-4#, Cdc2#, Cip", Cancer in Pathways Apoptosis Targeting acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer anti-inﬂammatory, leukemia, ﬁbrosarcoma, caspase-8", PARP", NF-kB#, antiangiogenesis, and neuroblastoma, thyroid HER2#, PI3K/Akt#, Bad", hepatoprotective effects carcinoma Bcl-X(S)", Bcl-X(L)#, MMP-2#, MMP-9#, caspase-3, -9", ERK", Raf-1", Ca(2þ)", Cyto-c", bcl-2#, LTC4?, LTB4?, IgE?, cPLA2?, 5-LO?, MMP-9?,Ca (2þ)", caspase-7", ADP- ribose#, phosphatase" (Continued on the following page) 1083 1084 Downloaded from acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer ilmuoe al. et Millimouno

Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Compound Natural source Mode of action Type of cancers Synergistic Major targets Jaceosidin Artemisia princeps, Artemisia Antioxidant, antiproliferation Human endometrial, human TNFa Cdc2#, cyclin B1#, complex?, cancerpreventionresearch.aacrjournals.org iwayomogi, Artemisia argyi, (cell-cycle arrest, apoptosis), ovary cancer, glioblastoma, caspase-9", MMP#, p53", Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 Artemisia copa, Artemisia anti-inﬂammation breast, epithelial, prostate, Bax", COX-2", MMP-9", TPA?, vestita, Saussurea medusa, cervical, mammary epithelial protein E6 and E7?, p53?, Eupatorium arnottianum, Bax", Bcl-2#, caspase-3",p53", Eupatorium lindleyanum, p21", ERK1/2? Centaurea phyllocephala, Centaurea nicaeensis, Nipponanthemum nipponicum, Arnica chamissonis, Arnica Montana, Vervain ofﬁcinalis,

Cancer Research. Lantana montevidensis, Eriodictyon californicum

Casticin Vitex rotundifolia, V. agnus Antioxidant, antiproliferation Cervical, pancreatic, colon, TRAIL, TNFa, cisplatin, JNK, Bcl-2#, Bcl-xL#, XIAP#, castus, V. trifolia, V. (cell-cycle arrest, apoptosis), breast, lung, gastric, ovarian, curcumin caspase-3", caspase-9", cyclin on September 28, 2021. © 2014American Association for negundo, Daphne genkwa, premenstrual syndrome, liver, colorectal, leukemia, B1#, Bax", TNF#, DR5", Achillea millefolium, Ficus Anti-inflammation, prostate MMP2#,MMP9#, NF-kB#, microcarpa, Fructus viticis, antianxiety, STAT3#, FOXO3a#, FoxM1#, Crataegus pinnatifida, immunomodulation, CDK1#, cdc25B#, cyclin B#, Pavetta crassipes, Nelsonia antimalarial, antimicrobial, p27KIP1", cyclin A#, cFLIP#, canescens, Citrus unshu, and antifungal properties survivin#, cytochrome c", Bid" Centipeda minima, Clausena excavate, Croton betulaster, Artemisia abrotanum L., Camellia sinensis acrPeeto Research Prevention Cancer Sesquiterpenes Costunolide Inula helenium, Saussurea Antioxidant, antiproliferation Liver, ovarian, breast, bladder, TNFa, taxol, cisplatin Bcl-2#, caspase-3",-8", and -9", lappa, Magnolia grandiflora (cell-cycle arrest, apoptosis), melanoma, leukemia, Bax", Fas",Cdc2#, cyclin B1#; anti-inflammation, prostate, human monocyte, p21WAF1", procaspase-8", anticancer, anti- gastric, colorectal procaspase-3"; JNK"; PI3-K; inflammatory, antiviral, PKC; ERK", NF-kB#, cyclin E#; antifungal p21", VEGF# (Continued on the following page) www.aacrjournals.org Downloaded from Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Tanacetum larvatum, antiangiogenesis, lung, bladder, prostate, bile acid, geldanamycin, transporter#, Bcl-X(L)#, Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 Helianthus Annuus, Anvillea autophagy, duct carcinomas, buthionine survivin#, cyclin D1#, IL8# matrix radiate, Magnolia kobus, immunomodulation, and pancreatic, myeloma, sulfoximine metalloproteinase 9#, Akt Magnolia virginiana, cytotoxic effects leukemia, colorectal, Burkitt phosphorylation#,NF-kB#, Magnolia ovate, Magnolia lymphoma, epithelial p65/NF-kB#, Ki67#,p21", grandiﬂora, Liriodendron ovarian, osteosarcoma antioxidant N-acetyl-L- tulipifera, Michelia, Magnolia cystein?, glutathione S- champaca, Michelia transferase# STAT3?, JAK?, ﬂoribunda, tBid" of caspase-3/8/9", poly Tsoongiodendron odorum, (ADP-ribose) polymerase?, Artemisia ludoviciana, Calea p-ERK", p-p38", p38 and zacatechichi, Polymnia SAPK/JNK", PKC-alpha?, Cancer Research. maculate, Achillea falcata procaspase-3#,p65#, VEGF?, IL6 mRNA?, IkappaB-alpha", p53", ROS", JNK", Bid"

on September 28, 2021. © 2014American Association for Alantolactone Inula helenium, L., Inula Anti-inﬂammatory, Prostate, glioblastoma, colon, — Bax/Bcl-2", caspase-3", STAT3?, japonica Aucklandia lappa, antimicrobial, anticancer, leukemia, liver, lung caspase-8, MMP#, Bid", NF-kB/ Radix inulae Inula racemosa cytotoxicity, antifungal, p65#, p53", Bax", Bcl-2#, oxidoreductase, and caspase-9", caspase-3", ADP- antiproliferative ribose#, NF-kB?, ROS", activin/ SMAD3 signaling", Cripto-1/ ActRII?, ROS", cytochrome-c", " # # Bax , PARP , ADP-ribose , NF- Cancer in Pathways Apoptosis Targeting acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer kB?, DNA-binding#,IkBa phosphorylation#,p21", Bcr/ Abl#, P-glycoprotein#, cyclin B1#, cyclin-dependent protein kinase-1#

Isoalantolactone Inula helenium, L., Inula Anti-inﬂammatory, Prostate gastric pancreatic — p38", MAPK", Bax", and cleaved japonica Aucklandia lappa, antimicrobial, anticancer, leukemia caspase-3", Bcl-2#, PI3K/Akt?, Radix inulae Inula racemosa cytotoxicity, antifungal, PARP" oxidoreductase, and antiproliferative (Continued on the following page) 1085 1086 Downloaded from acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer ilmuoe al. et Millimouno

Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Compound Natural source Mode of action Type of cancers Synergistic Major targets cancerpreventionresearch.aacrjournals.org

Diterpenoids Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 Oridonin Isodon rubescens Antioxidant, antiproliferation Breast, astrocytoma, leukemia, TRAIL, gemcitabin, Caspase-8#, NF-kB (p65)#, IKKa#, (cell-cycle arrest, apoptosis), lung, hepatoma, prostate, taxol, TNFa, cisplatin, IKKb#, phospho-mTOR#, Fas", anti-inﬂammation, colorectal, pancreatic, curcumin, arsenic PPARg", MMP-2/MMP-9#, b1/ autophagy, and ovarian, human multiple trioxide (As2O3), FAK?, caspase-3", LYN?, immunomodulation myeloma, human histocytic Wogonin ABL?, Akt/mTOR#, Raf/MEK/ lymphoma, hepatocellular, ERK# and STAT5#, AML1-ETO#, cervical, neuroblastoma, c-Kit(þ)?, c-Met-NF-kB-COX- laryngeal, gastric, murine 2", c-Met-Bcl-2-caspase-3, ﬁbrosarcoma, melanoma, Bcl-2/Bax ratio", AVOs#, LC3- epidermoid carcinoma, I?, LC3-II?, P21", FAS?, osteosarcoma SREBP1?, AP-1#,NF-kB#, Cancer Research. P38#, p21", p27", p16", c-myc p38", p53", (MAPK)-p38, cyclin B1 and p-cdc2 (T161)#, p53", Akt#, ROS#, SIRT1#, NF-kB", on September 28, 2021. © 2014American Association for caspase-1", IL1b",XIAP#, Grp78", a-CP1#, Bcl-2#, caspase-8", procaspase-3-9#, pro-TNFa", p53#, caspase-9#, DeltaPsim#,ERK#, p38", MAPK", JNK"

Pseudolaric Pseudolarix kaempferi Antioxidant, antiproliferation Microvessel endothelial, Taxol, TNFa NF-kB?, p65?, IL2#, IkB-a?, Acid B (cell-cycle arrest, apoptosis), prostate, glioblastoma, cyclin B1", CDK1", cyclin D1# immunomodulation, umbilical vein endothelial, p53", Bax", Bcl-2#,1a and anticancer and anti- murine ﬁbrosarcoma, cyclin E#, cdc2", cdc2#, acrPeeto Research Prevention Cancer inﬂammatory, and bladder, colon, lung, breast, survivin#, caspase-3", COX-2?, antiangiogenesis effects melanoma, ovarian, STAT3, I-kB#, Tubulin, binding leukemia, gastric, liver of colchicine to tubulin?, bcl-x(L) ?, NAG-1", JNK", ERK#, Wee1 kinase and p21", Bcl-xL#, Bax", caspase-7", Fas/APO-1", Bcl-2 binding with Beclin 1?, Akt phosphorylation# (Continued on the following page) www.aacrjournals.org Downloaded from cancerpreventionresearch.aacrjournals.org

Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd ) Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136

Compound Natural source Mode of action Type of cancers Synergistic Major targets Polyphenolic Wedelolactone Eclipta alba, Wedelia Antioxidant, antiproliferation Breast, prostate, IFNg NF-kB#, PARP",IIa#, p-p53", calandulaceae, Wedelia (cell-cycle arrest, apoptosis), neuroblastoma, pancreatic, caspase-3", caspase-7",c- chinensis, Eclipta prostrata anti-inﬂammation, and mammary carcinosarcoma, JNK", PKCe#, IKKa#, Bax", Bcl- hepatoprotective effects myeloma, leukemia, xL#, p21",p27", Bcl-2#, IL6#, adenoma, glioma IL6R#, c-myc, IKK#, p-TAK1, IKKb#, IKKa#, IL1b#, STAT-3#, TLR-4", TLR-7", TLR-8", Akt#, TNFa#,IkB# Cancer Research.

Alkaloids Evodiamine Evodia rutaecarpa Antioxidant, antiproliferation Murine Lewis lung, Gemcitabin, taxol, Atgs", 3-MA?, IL6#, STAT3?, (cell-cycle arrest, apoptosis), hepatocellular, leukemia, TNFa, cisplatin AP-1?, PLC- g1?,XIAP?, Bax",

on September 28, 2021. © 2014American Association for anti-inﬂammation, gastric, pancreatic, colon, CDK1?, ND cyclinB1", PI3K?, antimicrobial, anticancer, human thyroid cancer, Akt?, PKA?,mTOR?, PTEN?, antimetastatic, and melanoma, colorectal, NF-kB#, cyclinA#, cyclinA- anticarcinogenesis breast, cervix carcinoma, dependent kinase 2#, cdc25c#, prostate TUNEL", procaspase-3-8-9#, cdc25C", cyclin B1", cdc2- p161 protein", cdc2-p15, caspase-3-8-9", Fas-L",p53", agtn ppoi ahasi Cancer in Pathways Apoptosis Targeting acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer p21", Bcl-2#, TopI?, Raf-1#, Bax", Bcl-2", Bcl-x(L)#, Beclin 1", LC3", Cdc2", cyclin B1", Cdc2 (Thr 161) ", Cdc2 (Tyr 15) #, Myt-1#, Cdc25C#, caspase- 3-9", ERK phosphorylation#, VEGF? (Continued on the following page) 1087 1088 Downloaded from acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer ilmuoe al. et Millimouno

Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Compound Natural source Mode of action Type of cancers Synergistic Major targets cancerpreventionresearch.aacrjournals.org

Flavonoids Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 Honokiol Magnolia officinalis, Magnolia Antioxidant, antiproliferation Glioblastoma, melanoma, Fluconazole, CDK1?, Bcl-2#, Bax", cyclin D1#, grandiflora, Magnolia spp. (cell-cycle arrest, apoptosis), gastric, leukemia, skin, Epigallocatechi n pAKT#, g-secretase activity#, anti-inflammation, colon, breast, ovarian, gallate (EGCG), TNFa g-secretase complex proteins#, antiangiogenesis, pancreatic, hepatocellular, PPARg?, COX-2?, NF-kB?, antiautophagy, colorectal, lung, prostate, EGFR/P13K/AKt#; JunB#and immunomodulation, human renal mesangial, JunD# caspase-8", caspase-9", anticancer, gastrointestinal head and neck squamous caspase-3", PARP", p53", disorders, cough, anxiety, carcinoma CD31 staining#,LH",p38?, and allergies NF-kB?, Bcl-XL#, Bad", cyclin E#, (Cdk2 and Cdk4)#,Cdk", p21 and p27", NF-kB#, Bcl-2#, Cancer Research. Mcl-1#, surcivin#, VEGF#, STAT3?, HG-induced IL1b?, IL18?, TNFa?, -PGE2?,NO?, and TGFb1?, MCP-1 ?, MIP- on September 28, 2021. © 2014American Association for 1a?, EGFR targeting TKI?, Akt? erlotinib?, EGFR signaling?, MAPK?, cyclin D1?

Magnolol Magnolia officinalis, Magnolia Antiproliferation (cell-cycle Glioblastoma, bladder, breast, TNFa, curcumin p21/Cip1", p27/Kip1", Hypoxia?, obovata. arrest, apoptosis), colon, gastric, skin, ovarian, HIF1a", VEGF", AMPK", Bcl2#, immunomodulation, lung, prostate, melanoma, Bax", p53", Bax/Bcl-2", anticancer, antianxiety, liver cancer, cervical caspase-3", Cyclin B1#, Cyclin antidepressant, antioxidant, epitheloid carcinoma, A#, CDK-4#, Cdc2#, Cip", anti-inflammatory, leukemia, fibrosarcoma, caspase-8", PARP", NF-kB#, antiangiogenesis, and neuroblastoma, thyroid HER2#, -PI3K/Akt#,Bad", Bcl-X acrPeeto Research Prevention Cancer hepatoprotective effects carcinoma (S)", Bcl-X(L)#, MMP-2#,MMP- 9#, caspase-3, 9", ERK", Raf- 1", Ca(2þ) ", Cyto-c", bcl-2#, LTC4?,LTB4?, IgE?,cPLA2?, 5-LO?, MMP-9?, Ca(2þ)", caspase-7", ADP-ribose#, phosphatase" (Continued on the following page) www.aacrjournals.org Downloaded from

Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Compound Natural source Mode of action Type of cancers Synergistic Major targets Jaceosidin Artemisia princeps, Artemisia Antioxidant, antiproliferation Human endometrial, human TNFa Cdc2#, cyclin B1#, complex?, iwayomogi, Artemisia argyi, (cell-cycle arrest, apoptosis), ovary cancer, glioblastoma, caspase-9", MMP.#, p53", cancerpreventionresearch.aacrjournals.org Artemisia copa, Artemisia anti-inﬂammation breast, epithelial, prostate, Bax", COX-2", MMP-9", TPA?, Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 vestita, Saussurea medusa, cervical, mammary epithelial protein E6 and E7?, p53?, Eupatorium arnottianum, Bax", Bcl-2#, caspase-3",p53", Eupatorium lindleyanum, p21", ERK1/2? Centaurea phyllocephala, Centaurea nicaeensis, Nipponanthemum nipponicum, Arnica chamissonis, Arnica Montana, Vervain ofﬁcinalis, Lantana montevidensis,

Cancer Research. Eriodictyon californicum

Casticin Vitex rotundifolia, V. agnus Antioxidant, antiproliferation Cervical, pancreatic, colon, TRAIL, TNFa, cisplatin, Bcl-2#, Bcl-xL#, XIAP#, castus, V. trifolia, V. (cell-cycle arrest, apoptosis), breast, lung, gastric, ovarian, curcumin caspase-3", caspase-9", Cyclin # " # "

on September 28, 2021. © 2014American Association for negundo, Daphne genkwa, premenstrual syndrome, liver, colorectal, leukemia, B1 , Bax , TNF , DR5 , Achillea millefolium, Ficus anti-inﬂammation, prostate MMP2#,MMP9#, NF-kB#, microcarpa, Fructus viticis, antianxiety, STAT3#, FOXO3a#, FoxM1#, Crataegus pinnatiﬁda, immunomodulation, CDK1#, cdc25B#, cyclin B#, Pavetta crassipes, Nelsonia antimalarial, antimicrobial, p27KIP1", Cyclin A#, cFLIP#, canescens, Citrus unshu, and antifungal properties survivin#, cytochrome c", Bid" Centipeda minima, Clausena excavate, Croton betulaster, agtn ppoi ahasi Cancer in Pathways Apoptosis Targeting

acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer Artemisia abrotanum L., Camellia sinensis

Sesquiterpenes Costunolide Inula helenium, Saussurea Antioxidant, antiproliferation Liver, ovarian, breast, bladder, TNFa, taxol, cisplatin Bcl-2 #, caspase-3",-8", and -9", lappa, Magnolia grandiflora (cell-cycle arrest, apoptosis), melanoma, leukemia, Bax", Fas",Cdc2#, cyclin B1#; anti-inflammation, prostate, human monocyte, p21WAF1", pro-caspase-8", anticancer, anti- gastric, colorectal pro-caspase-3"; JNK"; PI3-K; inflammatory, antiviral, PKC; ERK", NF-kB#, cyclin E#; antifungal p21", VEGF# (Continued on the following page) 1089 1090 Downloaded from acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer ilmuoe al. et Millimouno Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Compound Natural source Mode of action Type of cancers Synergistic Major targets Parthenolide Tanacetum parthenium., Antioxidant, antiproliferation Breast, skin, melanoma, TTRAIL, gemcitabin, Bax", Bcl2#, mRNA# Tanacetum vulgare, (cell-cycle arrest, apoptosis), malignant glioma, epidermal taxol, TNFa, cisplatin, metalloproteinase-9#, STAT- cancerpreventionresearch.aacrjournals.org Centaurea ainetensis, anti-inflammation, tumorigenesis, liver, gastric, curcumin, okadaic 3?, JNK", VEGF?, IL8?, Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 Tanacetum larvatum, antiangiogenesis, lung, bladder, prostate, bile acid, geldanamycin, ABCB5 transporter#, Bcl-X(L) #, Helianthus Annuus, Anvillea autophagy, duct carcinomas, buthionine survivin#, cyclin D1#, IL8# matrix radiate, Magnolia kobus, immunomodulation, and pancreatic, myeloma, sulfoximine metalloproteinase 9#, Akt Magnolia virginiana, cytotoxic effects leukemia, colorectal, Burkitt phosphorylation#, NF-kB#, p65/ Magnolia ovate, Magnolia lymphoma, epithelial NF-kB#, Ki67#,p21", grandiflora, Liriodendron ovarian, osteosarcoma antioxidant N-acetyl-L- tulipifera, Michelia, Magnolia cystein?, glutathione S- champaca, Michelia transferase# STAT3?, JAK?, floribunda, tBid" of caspase-3/8/9", poly Tsoongiodendron odorum, (ADP-ribose) polymerase?,p-

Cancer Research. Artemisia ludoviciana, Calea ERK", p-p38", p38 and SAPK/ zacatechichi, Polymnia JNK", PKC-alpha?, pro- maculate, Achillea falcata caspase-3#, p65#, VEGF?, IL6 mRNA?, IkappaB-alpha", p53", " " " on September 28, 2021. © 2014American Association for ROS , JNK , Bid

Alantolactone Inula helenium, L., Inula Anti-inﬂammatory, Prostate, glioblastoma, colon, — Bax/Bcl-2", caspase-3", STAT3?, japonica Aucklandia lappa, antimicrobial, anticancer, leukemia, liver, lung caspase-8, MMP#, Bid", NF-B/ Radix inulae Inula racemosa cytotoxicity, antifungal, p65#, p53", Bax", Bcl-2#, oxidoreductase, and caspase-9", caspase-3", ADP- antiproliferative ribose#, NF-kB?, ROS", activin/ SMAD3 signaling", Cripto-1/ ActRII?, ROS", cytochrome-c", Bax", PARP#, ADP-ribose#, NF- B?, DNA-binding#,IkBa phosphorylation#, p21", Bcr/ acrPeeto Research Prevention Cancer Abl#, P-glycoprotein#, cyclin B1#, cyclin-dependent protein kinase-1#

Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Compound Natural source Mode of action Type of cancers Synergistic Major targets Diterpenoids # # #

cancerpreventionresearch.aacrjournals.org Oridonin Isodon rubescens Antioxidant, antiproliferation Breast, astrocytoma, leukemia, TRAIL, gemcitabin, Caspase-8 , NF-kB (p65) , IKKa , (cell-cycle arrest, apoptosis), lung, hepatoma, prostate, taxol, TNFa, cisplatin, IKKb#, phospho-mTOR#, Fas", Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 anti-inﬂammation, colorectal, pancreatic, curcumin, arsenic PPARg", MMP-2/MMP- 9#, b1/ autophagy, and ovarian, human multiple trioxide (As2O3), FAK?, caspase-3", LYN?, immunomodulation myeloma, human histocytic Wogonin ABL?, Akt/mTOR#, Raf/MEK/ lymphoma, hepatocellular, ERK# and STAT5#, AML1-ETO#, cervical, neuroblastoma, c-Kit(þ)?, c-Met-NF-kB-COX- laryngeal, gastric, murine 2", c-Met-Bcl-2-caspase-3, ﬁbrosarcoma, melanoma, Bcl-2/Bax ratio", AVOs#, LC3- epidermoid carcinoma, I?, LC3-II?, P21", FAS?, osteosarcoma SREBP1?, AP- 1#, NF-kB#, P38#, p21", p27", p16", c-myc

Cancer Research. p38", p53", (MAPK)-p38, cyclin B1 and p-cdc2 (T161)#, p53", Akt#, ROS#, SIRT1#, NF-kB", caspase-1", IL-1b",XIAP#,

immunomodulation, umbilical vein endothelial, p53", Bax", Bcl-2#,1 and Cancer in Pathways Apoptosis Targeting acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer a anticancer, and anti- murine ﬁbrosarcoma, cyclin E#, cdc2", cdc2#, inﬂammatory and bladder, colon, lung, breast, survivin#, caspase-3", COX-2?, antiangiogenesis effects melanoma, ovarian, STAT3, I-kB#, Tubulin, binding leukemia, gastric, liver of colchicine to tubulin?, bcl-x (L) ?, NAG-1", JNK",ERK#, Wee1 kinase and p21", Bcl-xL#, Bax", caspase-7", Fas/APO-1", Bcl-2 binding with Beclin 1?, Akt phosphorylation# (Continued on the following page) 1091 1092 Downloaded from acrPe e;71)Nvme 2014 November 7(11) Res; Prev Cancer ilmuoe al. et Millimouno cancerpreventionresearch.aacrjournals.org Published OnlineFirstAugust26,2014;DOI:10.1158/1940-6207.CAPR-14-0136 Table 1. Natural source, pharmacologic action, and molecular targets of promising natural compounds (Cont'd )

Compound Natural source Mode of action Type of cancers Synergistic Major targets Polyphenolic Wedelolactone Eclipta alba, Wedelia Antioxidant, antiproliferation Breast, prostate, IFNg NF-kB#, PARP",IIa#, p-p53", calandulaceae, Wedelia (cell-cycle arrest, apoptosis), neuroblastoma, pancreatic, caspase-3", caspase-7",c- chinensis, Eclipta prostrata anti-inﬂammation, and mammary carcinosarcoma, JNK", PKCe#, IKKa#,Bax", Bcl- hepatoprotective effects myeloma, leukemia, xL#, p21",p27", Bcl-2#, IL6#, adenoma, glioma IL6R#, c-myc, IKK#, p-TAK1, IKKb#, IKKa#, IL1b#, STAT-3#, TLR-4", TLR-7", TLR-8", Akt#, Cancer Research. TNFa#,IkB#

Alkaloids Evodiamine Evodia rutaecarpa Antioxidant, antiproliferation Murine Lewis lung, Gemcitabin, taxol, Atgs", 3-MA?, IL6#, STAT3?, on September 28, 2021. © 2014American Association for (cell-cycle arrest, apoptosis), hepatocellular, leukemia, TNF-a, cisplatin AP-1?, PLC-g1?, XIAP?, Bax", anti-inﬂammation, gastric, pancreatic, colon, CDK1?, ND cyclinB1", PI3K?, antimicrobial, anticancer, human thyroid cancer, Akt?, PKA?, mTOR?, PTEN?, antimetastatic, and melanoma, colorectal, NF-kB#, cyclinA#, cyclinA- anticarcinogenesis breast, cervix carcinoma, dependent kinase 2#, cdc25c#, prostate TUNEL", procaspase-3-8-9#, cdc25C", cyclin B1", cdc2- p161 protein", cdc2-p15, caspase-3-8-9", Fas- L",p53", p21", Bcl-2#, TopI?, Raf-1#, Bax", Bcl-2", Bcl-x(L) #, Beclin acrPeeto Research Prevention Cancer 1", LC3", Cdc2", cyclin B1", Cdc2 (Thr 161) ", Cdc2 (Tyr 15) #, Myt-1#, Cdc25C#, caspase-3- 9", ERK phosphorylation#, VEGF?

NOTE: #, downregulation; ", upregulation; ?, inhibition. Published OnlineFirst August 26, 2014; DOI: 10.1158/1940-6207.CAPR-14-0136

Targeting Apoptosis Pathways in Cancer

Table 2. Prevention of cancer with natural compounds

Cell-cycle Compounds Cancer type Tumor cell lines p53 status arrest References Flavonoids Magnolol Glioblastoma, bladder, breast, U373, T24, 5637, MDA-MB- — G0–G1 phase (39, 40, colon, gastric, skin, ovarian, 231, HCT- 116, SW480, 102, 115, lung, prostate, melanoma, SGC-7901, A431, SKOV3, 152–161) liver cancer, cervical TOV21G, CH27, A549, H460, epitheloid carcinoma, PC-3, A375-S2, B16-BL6, leukemia, ﬁbrosarcoma, COLO-205, HepG2, HEp-2, neuroblastoma, thyroid HeLa, 2H3, HT-1080, SH- carcinoma SY5Y, CGTH W-2

Casticin Cervical, pancreatic, colon, HeLa, CasKi, SiHa, PANC-1, Mutant G2–M phase (80, 132, 133, breast, lung, gastric, ovarian, MCF-7, A549, SGC-7901, p53 162–165) liver, colorectal, leukemia HO-8910, SKOV3, HepG2, PLC/PRF/5, MN1, MDD2, MCF-7, A431, HeLa, CCRF- CEM, CEM/ADR5000, P27kip1, P21waf1, pCDC2, K562, HL-60, Kasumi-1

Honokiol Glioblastoma, melanoma, A549, H1299, H460, H226, — G2–M phase (38–40, 156,

gastric, leukemia, skin, T98G, U251, B16-F10, G0–G1 phase 157, colon, breast, ovarian, UACC903, MKN45, SCM-1, 166–178) pancreatic, hepatocellular, NB4, K562, B-CLL, ChR, B- colorectal, lung, prostate, CLL, MT-2, MT-4, C5/MJ, human renal mesangial, SLB-1, HUT-102, MT-1, TL- head and neck squamous OmI, SKH-1, CT26, HT-29, carcinoma MCF-7, 4T1, MDA-MB -231, SKOV3, Coc1, A2780, Angelen MiaPaCa, Panc1, HepG2, HCT116, CT26, HCT116-CH2, HCT116-CH3, HepG2, A549, LL2, PC-3, LNCaP, HRMCs 1483, Cal-33

Jaceosidin Human endometrial, human Hec1A, CAOV-3, SKOV-3, — G2–M phase (134, 179–181) ovary cancer, glioblastoma, U87, MCF10A, SiHa, CaSki, breast, epithelial, cervical, MCF10A-ras mammary epithelial Sesquiterpenes

Costunolide Hepatocellular carcinoma, HCC, SKOV3, A2780, MPSC1, Mutant G2–M phase (112, 135, 160, ovarian, breast, bladder, MPSC1PT, A2780PT, p53 wild- 182–186) melanoma, leukemia, SKOV3PT, MDA-MB-231, type p53 prostate, human monocyte, MCF-7, MDA-MB-231, T24, gastric B-16, A2058, HT-29, HepG2, HL-60, U937, A549, SK- MEL-2, XF498, HCT-15, LNCaP, PC-3, DU-145, THP- 1, SGC-7901

Parthenolide Breast, skin, melanoma, MCF-7, MDMB-231, LCC9, — G2–M phase (187–201) malignant glioma, epidermal ABCB5þ, A375, 1205Lu, tumorigenesis, liver, gastric, WM793, U87MG, U373, lung, bladder, prostate, bile JB6Pþ, SH-J1, HepG2, duct carcinomas, Hep3B, SK-Hep1, MKN-28, pancreatic, myeloma, MKN-45, MKN-74, (Continued on the following page)

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Table 2. Prevention of cancer with natural compounds (Cont'd )

Cell-cycle Compounds Cancer type Tumor cell lines p53 status arrest References leukemia, colorectal, Burkitt SGC7901, A549, NSCLC, lymphoma, epithelial 5637, RT-4, PC3, DU145, ovarian, osteosarcoma VCAP, LAPC4, BxPC-3, PANC-1, MIAPaCa-2, RPMI8226, HL-60, U937, NB4, MV-4-11, MOLM-13, HT-29, SW620, LS174T, Rajiþ, OVCAR-3, K-OV-3, LM8, LM7

Alantolactone Liver, glioblastoma, colon, HepG2, Bel-7402, SMMC- — G2–M phase (49, 50, 105, leukemia, lung 7721, U87, HCT-8, HL-60, 125, 126) K562, K562, ADR, A549, MK-1, HeLa and B16F10

Isoalantolactone Prostate, pancreatic, leukemia, Hepa1c1c7, BPRc1, LNCaP, — G2–M phase (98, 124, 126, gastric PC3, DU-145, SGC-7901, 136) HL-60, HepG2-C8, PANC-1 Diterpenoids

Pseudolaric Microvessel endothelial, DU-145, PC-3, U87, HUVECs, — G2–M phase (141, 202–210) Acid B Prostate, glioblastoma, L929, 5637, HT-29, COLO- umbilical vein endothelial, 205, HCT-15, A-549, HOP- murine ﬁbrosarcoma, 18, MCF-7, MDA-MB-231, bladder, colon, lung, breast, MALME-3M, SK-MEL-2, SK- melanoma, ovarian, 28, OVCAR-3, SK-OV-3, HL- leukemia, gastric, murine 60, CCRF-CEM, K562, ﬁbrosarcoma, liver MGC803, L929, Bel-7402

Oridonin Breast, astrocytoma, leukemia, MCF-7, MDA-MB-231, C6, — G2–M phase (33, 124, lung, hepatom, prostate, Phþ ALL SUP-B15, t(8;21), 211–228) colorectal, pancreatic, L1210, A549, SPC-A-1, ovarian, human multiple K562, Bel-7402, PC-3, myeloma, human histocytic LNCaP, SW480, SW620, lymphoma, hepatocellular, SW1116, Lovo, SW480, cervical, neuroblastoma, BxPC-3, PANC-1, A2780, laryngeal, gastric, murine PTX10, RPMI8266, U937, ﬁbrosarcoma, melanoma, APL, HepG2, BEL7402, epidermoid carcinoma, HeLa, SK-N-AS, HEp-2, osteosarcoma MKN45, L929, K1735M2, A375-S2, A431, U2OS, MG63, SaOS-2 Polyphenolic

Wedelolactone Breast, prostate, MDA-MB-231, MDA-MB-468, — S and G2–M (229–237) neuroblastoma, pancreatic, PrEC, LNCaP, PC-3, DU145, phase mammary carcinosarcoma, 22Rv1, SK-N-AS, SK-N-BE, myeloma, leukemia, PANC-1, MIA-MSLN, W256, adenoma, glioma U266, B-CLL, GH3, C6 Alkaloids

Evodiamine Murine Lewis lung, LLC, HepG2, SMMC-7721, — G2–M phase (238–244) hepatocellular, leukemia, K562, THP-1, CCRF-CEM, gastric, pancreatic, colon, CCRF-CEM/C1, U937, human thyroid cancer, SGC-7901, SW1990, ARO, melanoma, colorectal, A375-S2, COLO-205, MCF- breast, cervix carcinoma, 7, NCI/ADR-RES, HeLa, prostate DU145, PC-3, LNCaP

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life forms to search for anticancer compounds (12). Indeed, natural products have traditionally provided a rich source of since 1920s with Berren blum, chemopreventive began drugs for cancer treatment (11). (11), after a period of relative dormancy, re-entered the Although different approaches are available for the dis- cancer research mainstream in the 1970s through the work covery of novel and potential therapeutic agents, natural of Sporn and colleagues (15). Till now, molecules derived products from medicinal plants are still one of the best from Mother Nature have played and continue to impart a reservoirs for novel agents with new medicinal activities. dominant role in the discovery of compounds for the Thus, identiﬁcation of natural compound selectively has development of conventional drug for the treatment of ability to not only block or inhibit initiation of carcino- most human diseases (16). genesis, but also to reverse the promotional stages by Medical indications of natural compounds and related inducing apoptosis and growth arrest in cancer cells without drugs, including anticancer, antibacterial, antiparasitic, cytotoxic effects in normal cells (18). The chemopreventive anticoagulant, and immune suppressant agents, are being properties and molecular targets of selected promising used to treat 87% of all categorized human diseases (12). natural compounds are detailed in Table 1, Figs. 2 and 3. Since 1970s, drug discovery was based on screening of a large number of natural and synthetic compounds; until with the advent of computer and other molecular biology Apoptosis Signaling Pathways techniques, resulting in the modern and rational drug Programmed cell death also called apoptosis play crucial discovery (17). The selected compounds and many other roles for embryonic development and tissue homeostasis of

Figure 2. Molecular targets of the promising natural compounds (change to BLACK/WHITE form). The schematic diagram of the molecular machinery and possible targets for the cell signaling pathways activated by natural compounds is different for different compounds. Multiple growth factor receptors such as, EGFR, insulin-like growth factor 1 receptor, FGF, and platelet-derived growth factor receptor are activated at the cell surface in tumorigenesis. Their activation activates several downstream signaling pathways including, Ras-MAPK (ERK and JNK) pathways, JAK-STAT pathways, PI3K-AKT pathways, and the NF-kB pathways. The selected natural compounds, for example, inhibit the receptors at the cell surface either by inducing their degradation, which ultimately modulate the downstream signaling pathways important for proliferation, angiogenesis, and apoptosis.

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Figure 3. Anticancer properties of the promising natural compounds (change to BLACK/WHITE form). The selected natural compounds restrain cancer by modulating multiple signaling pathways, resulting in the inhibition of the initiation of carcinogenesis, proliferation, angiogenesis, and oxidation so forth, and induction of cell-cycle arrest, apoptosis, autophagy, or differentiation.

multicellular organisms. It is carried out in a regulated vation. However, caspase-independent apoptosis is also way, which is associated with typical morphologic features reported (23). like cell shrinkage, chromatin condensation, and cyto- Apoptosis is characterized by chromatin condensation plasmic membrane blabbing. Dysregulated apoptosis has and DNA fragmentation, and it is mediated by caspases been implicated in a variety of diseases, including tumor (24). Many apoptotic signals are mediated to cell death formation or even development of cancer cell drug resis- machinery through p53 with other proteins such as TNF, tance (19). Fas, and TRAIL receptors that are highly specific physi- Apoptosis is triggered through two well-characterized ologic mediators of the extrinsic signaling pathway of pathways in mammalian cells. The first one is extrinsic apoptosis. Mitochondria are involved in a variety of key pathway, depending on triggering of death receptors events, such as release of caspases activators, changes in (e.g., TNF), transmembrane proteins expressed on the cell electron transport, loss of mitochondrial membrane surface, and the second is intrinsic pathway, mediated by potential (MMP), and participation of both pro-and molecules released from the mitochondria (e.g., Bcl-2 pro- antiapoptotic Bcl-2 family proteins (25, 26). This break- tein family; ref. 20). through finding may have important implication for The extrinsic apoptosis pathway is initiated through the targeted cancer therapy and modern application of nat- binding of ligand (Fas-associated death domain) to death ural compounds. receptors that contain an intracellular death domain (death- inducing signaling complexes; refs. 21, 22). The intrinsic pathway is activated by physical or chemical stimulations, Molecular Targets of Natural Chemopreventive such as hypoxia, growth factor deprivation, cell detach- Agents ment, or stress signals. Natural compounds, including flavonoids, sesquiter- A set of cysteine proteases, both pathways cause the penes lactones, alkaloid, diterpenoid, and polyphenolic activation of the initiator caspases, which then activate have been extensively studied and found to exhibit a broad effector caspases. Caspases are cysteine-dependent spectrum of chemo preventive properties against multiple aspartate-specific proteases and are regulated at a post- cancer types in both cell culture and animal models. translational level which ensures that they can be rap- Currently, several preventive trials are ongoing. For insis- idly activated. They are first synthesized or expressed tence, the cell signaling pathways activated by anticancer incellsasinactiveproenzymewhichconsistsofa natural compound agents are numerous and different for prodomain, a small subunit, and a large subunit forms different targets. Moreover, the same compound activates that require oligomerization and/or cleavage for acti- different signaling pathways depending on the cell types.

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The main signaling pathways activated by anticancer che- for malignant tumors is suppressed through c-Myc in p53- mopreventive agents are illustrated in Fig. 2. mutated Hs578T cells (44). The signaling pathways that depend on p53 are essential components of cellular responses to stress. Parthenolide in Targeting Cancer Cells by Regulating four cell lines, HCT116, RKO colon carcinoma, NCI-H1299 Apoptosis-Related Proteins Pathway lung carcinoma, and HL60 myeloblastoma, induced a sig- In normal cells, certain cellular signals control and reg- nificant reduction in the frequency of apoptotic cells in UV- ulate their growth and all other mechanisms. When these irradiated p53-proficient lines (45, 46). Parthenolide acti- signals and mechanisms are altered because of various vated p53 and other MDM2-regulated tumor-suppressor factors, including mutations that prevent cells to undergo proteins (47). Synergistic apoptotic effects of parthenolide apoptosis, normal cells are transformed into cancerous and okadaic acid treatment increased p53 accompanied by cells. Studies thus so far suggest that inhibition of any one lowering in p-Akt and pS166-Mdm2 levels under PTEN of these altered signals or mechanisms together is helpful in action (48). alleviation of cancer. It has also been documented that alantolactone signifi- cantly increased the expression of p53 in HepG2 cells (49, p53 and its family members pathway 50) with concomitant increase of its downstream target The tumor suppressor p53 considered as guardian of the genes, mainly cyclin-dependent kinase inhibitor p21 in genome plays a pivotal role in controlling the cell cycle, adriamycin-resistant human erythroleukemia cell line apoptosis, genomic integrity, and DNA repair in response to K562/ADR (51). Alantolactone induces p53-independent various genotoxic stresses (25, 27, 28). Once active, p53 can apoptosis in prostate cancer PC-3 cells (52). bind to regulatory DNA sequences and activate the expression of target genes, which is important for the suppression NF-kB and its family member pathway of tumor formation as well as for mediating the cellular The pro-oncogenic NF-kB is a master transcription factor responses to many standard DNA damage inducing cancer consisting of closely related proteins that generally exist as therapies by cycle inhibition (p21, reprimo, cyclin G1, dimers and bind to a common DNA sequence within the GADD45, 14-3-3) and angiogenesis (TSP1, Maspin, BAI1, promoters of target genes, called the kB B site, which GD-AIF), induction of apoptosis (PERP, NOXA, PUMA, promote transcription of target genes through the recruit- p53AIP1, ASPP1/2, Fas, BAX, PIDD), and genetic stability ment of coactivators and corepressors (53). The NF-kB (p21, DDB2, MSH2, XPC; refs. 29–32). pathway plays an important role in tumorigenesis through Recently, it has also been documented that many natural transactivation of genes involved in cell proliferation, apo- chemopreventive agents induce cell-cycle arrest and apoptosis, tumor cell invasion, metastasis, and angiogenesis ptosis by activating p53 and its target genes. Oridonin (54). The NF-kB1 family of transcription factors consists of induced upregulation of the functional p53 protein in five members, NF-kB1 (p50), NF-kB2 (p52), c-Rel, RelB, A2780 (33). Oridonin increased p53 and its target Bax and and RelA (p65), which share an N-terminal Rel homology p21waf1 in prostate cancer LNCaP and NCI-H520 cells with domain responsible for DNA binding and homodimeriza- wild-type p53 gene (33, 34). Oridonin also stabilizes p53 tion and heterodimerization through ankyrin repeats, cov- protein and sensitizes TRAIL (TNF receptor apoptosis- ering the nuclear localization sequence of NF-kB (53, 55). inducing ligand)-induced apoptosis, and prevents or delays In this momentum, NF-kB is normally sequestered in the chemotherapy resistance in A2780 cells (35). In human cytoplasm via association with its endogenous inhibitor prostate cancer, honokiol activated p21 (PC-3 and LNCaP) IkB. Furthermore, IkB-a is rapidly phosphorylated by and p53 protein expression (LNCaP; ref. 36). kinase IKK (IkB kinase) in two catalytic subunits, IKK-a Honokiol increased phosphorylated p53 in both and IKK-b, and one regulatory subunit IKK-g (56). HCT116H and CT116-CH3 cell lines (37). In skin cancer, NF-kB and other signaling pathways that are involved in p53 activation is lead to the induction of DNA fragmenta- its activation by free radicals, inflammatory stimuli, cyto- tion and apoptosis (38). Honokiol is particularly effective in kines, carcinogens, tumor promoters, endotoxins, g-radia- several tumor xenograft systems with deficits in p53 signal- tion, UV light, and X-rays are highly significant in cellular ing, including PC3, MDA-MD-231, and SVR cells (39). growth and transformation, suppression of apoptosis, inva- Furthermore, honokiol in a concentration- and time-depen- sion, metastasis, chemotherapy resistance, radio resistance, dent manner independent of their androgen responsiveness and inflammation (57). Furthermore, other agents includ- or p53 status induced Bax, Bak, and Bad in PC-3, LNCaP, ing TNFa, IL1, IL6, and COX-2, 5 in an inflammatory and C4-2 cells (40). p53 expression had no remarkable microenvironment are also highly involved in tumor pro- changes in honokiol induced in human colorectal RKO cell gression, incursion of adjoining tissues, angiogenesis, and line (41). metastasis (58). Casticin also induced p53-mediated apoptosis by acti- Activation of NF-kB inhibits apoptosis by inducing the vating its proapoptotic protein Bax in U251, U87, and U373 expression of Bcl-2 family members and caspases inhibitor glioma cells (42). Casticin induces a p53-independent (59). The major activity of NF-kB and its family members apoptosis in a human non–small cell lung carcinoma cell is to help proteolytic matrix metalloproteinase’s enzyme lines H460, A549, and H157 (43). Mechanism of casticin that promotes tumor invasion. Hence, IKKa promotes

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metastasis in prostate cancer via inhibition of mammary Nrf2-dependent expression of antioxidant enzymes (84, serine protease inhibitor (maspin; refs. 60, 61) and also 85). Costunolide and CH2-BL induced HO-1 expression stimulates angiogenesis, by activating IL8 and VEGF (58). and Nrf2 nuclear accumulation in RAW264.7 macrophages However, accumulation of the IkBa protein through pro- (86). Oridonin activates Nrf2 signaling pathway, leading to teasome inhibition prevents the activation of antiapoptotic accumulation of the Nrf2 protein and activation of the Nrf2- NF-kB resulting in tumor cell apoptosis (62). dependent cytoprotective response (87). Isoalantolactone The detail of these studies validated NF-kB as a potent and stimulates the accumulation of Nrf2 in the nucleus of both novel target for cancer therapy. They demonstrated that NF- Hepa1c1c7 cells and its mutant BPRc1 cells (88). Alanto- kB signaling pathways played critical role in a wide variety lactone also stimulated the nuclear accumulation of Nrf2 in of biologic, physiologic, and pathologic processes, mainly HepG2-C8 cells (89). in promoting cell survival through induction of its target genes. Each study individually taken, stimulate the moti- Transducers and activators of transcription and its vation and dedicated insight for developing natural com- family member pathways pound NF-kB inhibitors. STAT is a novel signal transduction pathway to the Many studies have been carried out on whether natural nucleus that has been uncovered through the study of compound-related cancer inhibits expression of NF-kBor transcriptional activation in response to IFN. It has been not. All the selected natural compound chemopreventive implicated in many processes including development, dif- agents act as potent inhibitors of the NF-kB pathways. ferentiation, immune function, proliferation, survival, and Wedelolactone, an inhibitor of IkB kinase, suppressed both epithelial-to-mesenchymal transition (90, 91). TNFa-induced IkB phosphorylation and NF-kB phosphor- Activation of various tyrosine kinases leads to phosphorylation at Ser 536 and Ser 468 (63), parthenolide (64–66), ylation, dimerization, and nuclear localization of the STAT and honokiol (67, 68). Costunolide inhibited the activa- proteins, binding to specific DNA elements and direct tion of Akt and NF-kB and the expression of antiapoptotic transcription. Constitutive activation of STAT3 and STAT5 factors B-cell lymphoma-extra large (Bcl-xL) and X-linked has been reported to be implicated in many cancers such as inhibitor of apoptosis protein (XIAP) in 11Z cells (69–71), myeloma, lymphoma, leukemia, and several solid tumors magnolol inhibits ERK1/2 phosphorylation and NF-kB (90–92). Furthermore, seven mammalian STAT family translocation (72, 73), PI3K/Akt/caspase and Fas-L/NF-kB members known such as STAT1, STAT2, STAT3, STAT4, signaling pathways might account for the responses of STAT5A, STAT5B, and STAT6 have been cloned and share A375-S2 cell death induced by evodiamine (74, 75). Ori- common structural elements. donin (76), alantolactone (77, 78), isoalantolactone (79), During the last decade, the natural compounds have been casticin (80), pseudolaric acid B (81), and jaceosidin (82), implicated to modulate STAT activation in tumor cells. each of them has an inhibitory effect on NF-kB and its Some selected agents are part, such as honokiol increases associated proteins. These compounds may inhibit one or expression and activity of SPH-1 that further deactivates the more steps in NF-kB signaling pathway and its upstream STAT3 pathway (93), wedelolactone inhibits STAT1 growth factor receptors that activate the signaling cascade, dephosphorylation through specific inhibition of T-cell translocation of NF-kB to the nucleus, DNA binding of the protein tyrosine phosphatase, which is important tyrosine dimers, or interactions with the basal transcriptional phosphatase for STAT1 (94). Parthenolide shows strong machinery. Thereupon, they can induce apoptosis in cancer STAT inhibition-mediated transcriptional suppression of cells, offering a promising strategy for the treatment of proapoptotic genes (64–66), and alantolactone inhibits different malignancies including cancer (Table 1 and Fig. STAT3 activation in HepG2 cells (49). Therefore, these 2; ref. 83). cumulative observations from both in vitro and/or in vivo studies have not only validated STAT as a novel target for Nuclear factor-related factor 2 signaling pathway cancer chemotherapy, and also hence provided the ratio- In cancer chemoprevention, nuclear factor-related factor nale for developing natural compound STAT inhibitors. 2 (Nrf2) is a potential molecular target for natural compounds. Several selected natural compounds are reported as Growth factors and their receptors family pathway a potential candidate for chemoprevention, by stimulating Growth factors are proteins that bind to receptors on the the accumulation of NrF2 in the nucleus and play a major cell surface and are reported to regulate a number of cellular role in transcriptional activation of phase II detoxification processes, with the primary result of activating cellular enzymes. Low concentrations of parthenolide led to Nrf2- proliferation and differentiation (95), apoptosis, and rear- dependent HO-1 induction accompanied by the attenua- rangement of cytoskeleton (96). Several growth factor sig- tion of its apoptogenic effect in Choi-CK and SCK cells. naling molecules are implicated in carcinogenesis. Among Furthermore, with the protein kinase C-a inhibitor them are endothelial growth factor, platelet-derived growth Ro317549 (Ro), parthenolide-mediated apoptosis inhibits factor, FGF, transforming growth factor, insulin-like growth expression and nuclear translocation of Nrf2, resulting in factor, and colony-stimulating factor (97). blockage of HO-1 expression. Parthenolide also stimulated As an important intracellular pathway consequence of oxidation of KEAP1 in normal prostate epithelial cells, growth factor receptor activation, several downstream sig- leading to increased Nrf2 (NFE2L2) levels and subsequent nalings, such as PI3K-Akt and Ras-MAPK also become

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active. These signaling pathways have significant impacts on toxicity is the key piece of natural compounds’ process the fact that it is associated with poor prognosis, tumor (110). Several reports reveal that the effects of selected progression, and become targets for many natural chemo- natural compounds on the intrinsic and extrinsic pathways preventive and chemotherapeutic agents. of apoptosis have been examined in many cell lines, includ- Isoalantolactone inhibits phosphorylation of PI3K/Akt ing HL-60, costunolide induces the reactive oxygen species on SGC-7901 cells (98), and alantolactone seems to induce (ROS)–mediated mitochondrial permeability transition detoxifying enzymes via activation of the PI3K and JNK and resultant cytochrome c release associated with signaling pathways (89). In cervical carcinoma HeLa cell increased expression of Bax, downregulation of Bcl-2, sur- line, oridonin may suppress constitutively activated targets vivin and significant activation of caspase-3, and its down- of phosphatidylinositol 3-kinase (Akt, FOXO, and GSK3; stream target PARP (111, 112). Honokiol induced release of ref. 99). In pancreatic cancer, evodiamine augments the cytochrome c into cytosol and a loss of MMP (Dcm), therapeutic effect of gemcitabine through direct or indirect associated with inhibition of EGFR-STAT3 signaling and negative regulation of the PI3K/Akt pathway (100) and also downregulation of STAT3 target genes and downregulation in A375-S2 cells (74). of Bcl-2 and upregulation of Bax expression in MDR KB and Magnolol protects SH-SY5Y cells against acrolein- RASMCs cells (113, 114). Magnolol induced apoptosis in induced oxidative stress and prolongs SH-SY5Y cell survival MCF-7 and HCT-116 cells via the intrinsic pathway with through regulating the JNK/mitochondria/caspase, PI3K/ release of AIF from mitochondria accompanied by down- MEK/ERK, and PI3K/Akt/FoxO1 signaling pathways (101). regulation of antiapoptotic protein Bcl-2 and upregulation In addition, in SGC-7901 cells, magnolol induces apoptosis of proapoptotic protein p53 and Bax (115, 116). To get a through mitochondria and PI3K/Akt-dependent pathways better insight into the mechanism of delaying cellular aging (102). Magnolol also suppressed the activation of MAPKs by mitochondria-targeted natural compound-induced cyto- (ERK, JNK, and p38) and the PI3K/AKT/mTOR signaling toxicity, the changes in membrane permeability, MMP, and pathway in mES/EB-derived endothelial-like cells cytochrome c localization, which influence mitochondrial (23708970). Honokiol decreases the PI3K/mTOR pathway biologic mechanisms, development of mitochondria- activity in tumor cells, but not in freshly stimulated T cells addressed compounds highly specific for chemical process- (103). It seems to be mediated by interrupting the early es is one of the most promising ways to develop approaches activated intracellular signaling molecule PI3K/Akt, but not for chemotherapy. Src, the extracellular signal-regulated kinase, and p38 (104). These reports showed that natural compounds, mainly the Targeting Cancer Cells by ROS-Mediated selected one, rapidly induce the phosphorylation of Akt after the stimulation and they can be used as a potent Apoptosis Pathway inhibitor against cancer cells. The human body constantly generates free radicals such as superoxide (O2 ), hydrogen peroxide (H2O2), nitric Cripto-1 and its allied protein signaling pathways oxide, peroxynitrile, and hypochlorous acid and other ROS In the process of normal cellular function, the dysfunc- as a result of aerobic metabolism (117, 118). ROS are tion of activin signaling constituted an active part of tumor cellular signals generated ubiquitously by all mammalian formation. To address this phenomenon, activin is blocked cells, and long-term exposure to physiologic or psychologic in cancer cells by the complex formed by Cripto-1, activin, stress is associated with the production of oxidative species and activin receptor type II (ActRII). In human colon through intracellular damage to DNA, RNA, proteins, and adenocarcinoma HCT-8 cells, alantolactone performs its lipids but their regulation induced cell proliferation, dif- antitumor effect by interrupting the interaction between ferentiation, and apoptosis, which are essential for proper Cripto-1 and the ActRIIA in the activin signaling pathway cell functioning (119, 122). ROS are well known mediators (105). of intracellular signaling of cascades. During cellular redox, the excessive generation of ROS can induce oxidative stress, loss of cell functioning, and apoptosis (123). Targeting Cancer Cells by Mitochondria- Induction of apoptosis of cancer cells by n-hexane frac- Mediated Apoptosis Pathway tion of sesquiterpene is mediated through activation of Mitochondria dysfunction is the key link in the chain of proteases, which act on specific substrates leading to the development of pathologies associated with the violation of degradation of PARP and other cytoskeletal proteins, cellular energy metabolism, including cancer. Mitochon- responsible for many of the morphologic and biochemical dria have become an important component of the apoptosis features of apoptosis in cancer cells (49, 50, 124–126). execution machinery, cytochrome c, initiator in the mito- Furthermore, once caspases activated, it might target the chondrial apoptosis pathway, and can be released from the permeability of mitochondria, resulting in the loss of MMP intermembrane of mitochondria after mitochondria depo- concomitant with increased production of ROS, and this larization (106–108). activity eventually causes disruption of membrane integrity Recently, many studies reported that the mitochondria (123). In addition, several studies revealed that apoptosis play a fundamental role in the processes leading to cell induction in chemotherapy depends on many factors like death (109). Identification of the loss of MMP through increase in ROS, oxidation of cardiolipin, reduced MMP,

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and release of cytochrome c (124). To restored cell viability, cyclin and cyclin-dependent kinase (Cdk) that triggers N-Acetyl Cysteine (NAC), a specific ROS inhibitor blocks entrance of a cell into mitosis by inducing chromatin completely apoptosis mediated by several natural com- condensation and nuclear envelope breakdown; it is also pounds such as isoalantolactone in PANC-1 cells. The called maturation-promoting factor. Another checkpoint activation of p38 MAPK and Bax is directly dependent on operates during early mitosis to prevent activation of ade- ROS generation. nomatous polyposis coli and the initiation of anaphase Cancer chemotherapy involves deregulation of cell pro- until the mitotic spindle apparatus is completely assembled liferation and survival, inducing cell-cycle arrest, cell death, and all chromosome kinetochores are properly attached to and apoptosis by generating ROS and their various enzyme spindle fibers. Checkpoints that function in response to systems, including the mitochondrial electron transport DNA damage prevent entry into S or M until the damage is chain, cytochrome, lipoxygenase, COX, the NADPH repaired (144–146). oxidase complex, xanthine oxidase, and peroxisomes When these signals are altered because of various muta- (127, 128). tions that prevent cells from undergoing apoptosis, normal Several studies reported that the promising natural com- cells are transformed into cancerous cells and undergo high pounds influenced the generation of ROS. In microglial proliferation. Therefore, to arrest cancerous cell prolifera- cells, honokiol and magnolol-induced apoptosis associated tion, regulation of apoptosis and its signaling pathways play with the inhibition of IFNg LPS-induced iNOS expression, a critical role (8, 147, 148). This behavior may lead to cell- NO, and ROS production (129, 130). Jaceosidin increased cycle arrest and upregulation of proapoptotic-related pro- intracellular accumulation of ROS in MCF10A-ras cells teins expression (49–51). In addition, it also documented (131). In HeLa, CasKi, SiHa cell lines, casticin markedly that the selected natural compounds induced cell-cycle increased the levels of intracellular ROS (132, 133). Parthe- arrest either G2–M, or S or G0–G1 phase. We have reviewed nolide enhanced geldanamycin-induced changes in the the effects of various signaling pathways that have been apoptosis-related protein levels, ROS formation, nuclear reported in selected natural compound-induced apoptosis damage, and cell death in human epithelial ovarian carci- (Fig. 3 and Table 2). noma OVCAR-3 and SK-OV-3 cell lines (134). Induction of apoptosis in T24 and MDA-MB-231 cells by Cancer Clinical Study costunolide is associated with the generation of ROS and Antiangiogenic therapy is at the forefront of drug devel- disruption of MMP (Dcm; ref. 112). In ovarian cancer cell opment. Knowledge of the multiple activities of natural lines [MPSC1 (PT), A2780 (PT), and SKOV3 (PT)], costu- compounds can assist with the development of natural nolide induced a significant increase in intracellular ROS compound derivatives and the design of preclinical and (135). The specific ROS inhibitor, NAC, restored cell via- clinical trials that will maximize the potential benefit of bility and completely blocked isoalantolactone-mediated natural compounds in the patient setting for cancer dis- apoptosis indicating that isoalantolactone induces ROS- orders. Thereupon, the natural compounds have been dependant apoptosis through intrinsic pathway in human examined in human and recently reported. Parthenolide pancreatic PANC-1 cells (124). It also induced apoptosis in was found to inhibit the expression of matrix metallopro- both androgen-sensitive (LNCaP) as well as androgen- teinase-9 and urinary plasminogen activator and the migra- independent (PC3 and DU-145) prostate cancer cells with tion of carcinoma cells in vitro, as well as osteolytic bone the generation of ROS and dissipation of MMP (Dcm; metastasis associated with breast cancer in vivo (149). At ref. 136). Alantolactone induced apoptosis accompanied doses up to 4 mg daily by oral capsule to treat fever, it is by ROS generation and mitochondrial transmembrane barely detectable in the plasma (150) . In combination with potential dissipation (49, 137). In hepatic stellate, HeLa, ciclopirox, parthenolide demonstrates greater toxicity and U937 cells, oridonin induced biologic processes, main- against acute myeloid leukemia than treatment with either ly intracellular ROS generation (138, 139). Pseudolaric acid compound alone (151). B induced ROS generation and mitochondrial dysfunction in L929 cells (140). It also caused the elevation of ROS level in DU145 cells (141). In human malignant melanoma Conclusion and Future Perspectives A375-S2 and cervix carcinoma HeLa cells, evodiamine Natural products have been, and continue to be, a induced apoptotic process associated with ROS release highly useful source of bioactive molecules. In this through both extrinsic and intrinsic pathways (142, 143). review, we have highlighted the recent progress of the natural compounds from Mother Nature with cytotoxic – activities. Plants provide a broad spectrum of sources for Targeting Cancer Cells by Cell-Cycle Mediated modern anticancer drugs. Various preclinical findings and Apoptosis Pathway results of several in vitro and in vivo studies convincingly Checkpoint controls function to ensure that chromo- argue for potent role of natural compounds in the pre- somes are intact and that critical stages of the cell cycle are vention and treatment of many types of cancer. Many completed before the following stage is initiated. One reports on mechanism of actions of the promising com- checkpoint operates during S and G2 to prevent the acti- pounds target multiple signaling pathways, which vary vation of mitosis-promoting factor, which is composed of a widely depending on cancer origin (11, 51).

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According to the literature, the major molecular targets small molecules to further validate the usefulness of these that have been characterized are the key challenge for agents as potent anticancer agents. researchers and scientists to use this information for effective cancer prevention in populations with different Disclosure of Potential Conﬂicts of Interest cancer risks. Moreover, low potency and poor bioavail- No potential conﬂicts of interest were disclosed. ability of natural compounds pose further challenges to Grant Support scientists and researchers. The future, full with conver- This work was supported by Ministry of Science and Technology (No. gence of chemoprevention and chemotherapy drug devel- 2010DFA31430), Ministry of Education of China (NCET-10–0316), National opment will open new avenues for natural compounds in Natural Science Foundation of China (No. 30871301, 30700827), Jilin Pro- vincial Science & Technology Department (20130521010JH, YYZX201241), reducing the public health impact of major cancers. Changchun Science & Technology Department (No. 2011114-11GH29), the However, additional preclinical studies and clinical trials Program for Introducing Talents to Universities (No. B07017), and the are certainly yet required to elucidate the full spectrum of Fundamental Research Funds for the Central Universities (12SSXM005). cytotoxic activities of the selected natural compounds Received April 24, 2014; revised July 23, 2014; accepted August 6, 2014; either alone or in synergistic combination with other published OnlineFirst August 26, 2014.

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www.aacrjournals.org Cancer Prev Res; 7(11) November 2014 1107

Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature

Faya M. Millimouno, Jia Dong, Liu Yang, et al.

Cancer Prev Res 2014;7:1081-1107. Published OnlineFirst August 26, 2014.

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