Planta Med 2019; 85(11/12): 802-814
DOI: 10.1055/a-0832-2383
Biological and Pharmacological Activity
Reviews
Georg Thieme Verlag KG Stuttgart · New York

Natural Product Triterpenoids and Their Semi-Synthetic Derivatives with Potential Anticancer Activity[*]

Yulin Ren
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States
,
A. Douglas Kinghorn
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States
› Author Affiliations
Further Information

Publication History

received 30 November 2018
revised 31 December 2018

accepted 05 January 2019

Publication Date:
18 January 2019 (online)


Abstract

Triterpenoids are distributed widely in higher plants and are of interest because of their structural diversity and broad range of bioactivities. In particular, there is a very large literature on the propensity of a variety of triterpenoids to act as potential anticancer agents. In the present review, the anticancer potential is summarized for naturally occurring triterpenoids and their semi-synthetic derivatives, including examples of lupane-, oleanane-, ursane-, and cucurbitane-type pentacyclic triterpenoids, along with dammarane-type tetracyclic triterpenes including ginsenosides and their sapogenins and dichapetalins, which have been characterized as antitumor leads from higher plants. Preliminary structure-activity relationships and reported mechanisms of the antineoplastic-related activity are included. Prior studies for triterpenoids of plant origin are supportive of additional work being conducted on the more detailed biological and mechanistic evaluation for the progression of this type of natural products as possible cancer chemotherapeutic agents.

* Dedicated to Professor Dr. Cosimo Pizza in recognition of his important contributions to natural product research on the occasion of his 70th birthday in 2019.


 
  • References

  • 1 Cragg GM, Kingston DGI, Newman DJ. eds. Anticancer Agents from Natural Products. 2nd ed.. Boca Raton: CRC Press/Taylor & Francis; 2012
  • 2 Butler MS, Robertson AAB, Cooper MA. Natural product and natural product derived drugs in clinical trials. Nat Prod Res 2014; 31: 1612-1661
  • 3 Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016; 79: 629-661
  • 4 Xu R, Fazio GC, Matsuda SPT. On the origins of triterpenoid skeletal diversity. Phytochemistry 2004; 65: 261-291
  • 5 Petronelli A, Pannitteri G, Testa U. Triterpenoids as new promising anticancer drugs. Anticancer Drugs 2009; 20: 880-892
  • 6 Hill RA, Connolly JD. Triterpenoids. Nat Prod Rep 2017; 34: 90-122
  • 7 Hong DS, Kurzrock R, Supko JG, He X, Naing A, Wheler J, Lawrence D, Eder JP, Meyer CJ, Ferguson DA, Mier J, Konopleva M, Konoplev S, Andreeff M, Kufe D, Lazarus H, Shapiro GI, Dezube BJ. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2012; 18: 3396-3406
  • 8 Baglin I, Mittaine-Offer AC, Nour M, Tan K, Cavé C, Lacaille-Dubois MA. A review of natural and modified betulinic, ursolic, and echinocystic acid derivatives as potential antitumor and anti-HIV agents. Mini Rev Med Chem 2003; 3: 525-539
  • 9 Setzer WN, Setzer MC. Plant-derived triterpenoids as potential antineoplastic agents. Mini Rev Med Chem 2003; 3: 540-546
  • 10 Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med 2009; 75: 1549-1560
  • 11 Kuo RY, Qian K, Morris-Natschke SL, Lee KH. Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents. Nat Prod Rep 2009; 26: 1321-1344
  • 12 Salvador JAR, Moreira VM, Gonçlaves BMF, Leal AS, Jing Y. Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs. Nat Prod Rep 2012; 29: 1463-1479
  • 13 Shanmugam MK, Nguyen AH, Kumar AP, Tan BKH, Sethi G. Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: potential role in prevention and therapy of cancer. Cancer Lett 2012; 320: 158-170
  • 14 Kamble SM, Goyal SN, Patil CR. Multifunctional pentacyclic triterpenoids as adjuvants in cancer chemotherapy: a review. RSC Adv 2014; 4: 33370-33382
  • 15 Salvador JAR, Leal AS, Valdeira AS, Gonçlaves BMF, Alho DPS, Figueiredo SAC, Silvestre SM, Mendes VIS. Oleanane-, ursane-, and quinone methide freidelane-type triterpenoid derivatives: recent advances in cancer treatment. Eur J Med Chem 2017; 142: 95-130
  • 16 Peron G, Marzaro G, DallʼAcqua S. Known triterpenes and their derivatives as scaffolds for the development of new therapeutic agents for cancer. Curr Med Chem 2018; 25: 1259-1269
  • 17 Kinghorn AD, Farnsworth NR, Soejarto DD, Cordell GA, Pezzuto JM, Udeani GO, Wani MC, Wall ME, Navarro HA, Kramer RA, Menendez AT, Fairchild CR, Lane KE, Forenza S, Vyas DM, Lam KS, Shu YZ. Novel strategies for the discovery of plant-derived anticancer agents. Pure Appl Chem 1999; 71: 1611-1618
  • 18 Kinghorn AD, Carcache de Blanco EJ, Lucas DM, Rakotondraibe HL, Orjala J, Soejarto DD, Oberlies NH, Pearce CJ, Wani MC, Stockwell BR, Burdette JE, Swanson SM, Fuchs JR, Phelps MA, Xu L, Zhang X, Shen YY. Discovery of anticancer agents of diverse natural origin. Anticancer Res 2016; 36: 5623-5637
  • 19 Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, Beecher CWW, Fong HHS, Kinghorn AD, Brown DM, Wani MC, Wall ME, Hieken TJ, Das Gupta TK, Pezzuto JM. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1995; 1: 1046-1051
  • 20 Henkin JM, Ren Y, Soejarto DD, Kinghorn AD. The Search for Anticancer Agents from Tropical Plants. In: Kinghorn AD, Falk H, Gibbons S, Kobayashi J, Asakawa Y, Liu JK. eds. Progress in the Chemistry of Organic Natural Products, vol. 107. Cham: Springer International; 2018: 1-94
  • 21 Zhang DM, Xu HG, Wang L, Li YJ, Sun PH, Wu XM, Wang GJ, Chen WM, Ye WC. Betulinic acid and its derivatives as potential antitumor agents. Med Res Rev 2015; 35: 1127-1155
  • 22 Ali-Seyed M, Jantan I, Vijayaraghavan K, Bukhari SNA. Betulinic acid: Recent advances in chemical modifications, effective delivery, and molecular mechanisms of a promising anticancer therapy. Chem Biol Drug Des 2016; 87: 517-536
  • 23 Pettit GR, Melody N, Hempelstall F, Chapuis JC, Groy TL, Williams L. Antineoplastic agents. 595. Structural modifications of betulin and the X-ray crystal structure of an unusual betulin amine dimer. J Nat Prod 2014; 77: 863-872
  • 24 Ye Y, Zhang T, Yuan H, Li D, Lou H, Fan P. Mitochondria-targeted lupane triterpenoid derivatives and their selective apoptosis-inducing anticancer mechanisms. J Med Chem 2017; 60: 6353-6363
  • 25 Kim DSHL, Pezzuto JM, Pisha E. Synthesis of betulinic acid derivatives with activity against human melanoma. Bioorg Med Chem Lett 1998; 8: 1707-1712
  • 26 Tsepaeva OV, Nemtarev AV, Abdullin TI, Grigorʼeva LR, Kuznetsova EV, Akhmadishina RA, Ziganshina LE, Cong HH, Mironov VF. Design, synthesis, and cancer cell growth inhibitory activity of triphenylphosphonium derivatives of the triterpenoid betulin. J Nat Prod 2017; 80: 2232-2239
  • 27 Pettit GR, Melody N, Chapuis JC. Antineoplastic agents. 606. The betulastatins. J Nat Prod 2018; 81: 458-464
  • 28 Seneja A, Sharma L, Dubey RD, Mintoo MJ, Singh A, Kumar A, Sangwan PL, Tasaduq SA, Singh G, Mondhe DM, Gupta PN. Synthesis, characterization and augmented anticancer potential of PEG-betulinic acid conjugate. Mat Sci Eng C 2017; 73: 616-626
  • 29 Shanmugam MK, Dai X, Kumar AP, Tan BKH, Sethi G, Bishayee A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: preclinical and clinical evidence. Cancer Lett 2014; 346: 206-216
  • 30 Lúcio KA, Rocha GG, Moncão-Ribeiro LC, Fernandes J, Takiya CM, Gattass CR. Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastatis of a B16F10 melanoma model in vivo . PLoS One 2011; 6: e28596
  • 31 Li HF, Wang XA, Xiang SS, Hu YP, Jiang L, Shu YJ, Li ML, Wu XS, Zhang F, Ye YY, Weng H, Bao RF, Cao Y, Lu W, Dong Q, Liu YB. Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells. Drug Des Dev Ther 2015; 9: 3017-3030
  • 32 Takemura M, Endo S, Matsunaga T, Soda M, Zhao HT, El-Kabbani O, Tajima K, Iinuma M, Hara A. Selective inhibition of the tumor marker aldo-keto reductase family member 1B10 by oleanolic acid. J Nat Prod 2011; 74: 1201-1206
  • 33 Shi Y, Song Q, Hu D, Zhuang X, Yu S, Teng D. Oleanolic acid induced autophagic cell death in hepatocellular carcinoma cells via PI3K/Aκt/mTOR and ROS-dependent pathway. Korean J Physiol Pharmacol 2016; 20: 237-243
  • 34 Bernabé-García Á, Armero-Barranco D, Liarte S, Ruzafa-Martínez M, Ramos-Morcillo AJ, Nicolás FJ. Oleanolic acid induces migration in Mv1Lu and MDA-MB-231 epithelial cells involving EGF receptor and MAP kinases activation. PLoS One 2017; 12: e0172574
  • 35 Xu Y, Shu B, Tian Y, Wang G, Wang Y, Wang J, Dong Y. Oleanolic acid induces osteosarcoma cell apoptosis by inhibition of Notch signaling. Mol Carcinog 2018; 57: 896-902
  • 36 Luo Y, Liu Z, Zhang X, Huang J, Yu X, Li J, Xiong D, Sun X, Zhong Z. Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo . Int J Nanomed 2016; 11: 3111-3129
  • 37 Honda T, Rounds BV, Bore L, Finlay HJ, Favaloro FG, Suh N, Wang Y, Sporn MB, Gribble GW. Synthetic oleanane and ursane triterpenoids with modified rings A and C: A series of highly active inhibitors of nitric oxide production in mouse macrophages. J Med Chem 2000; 43: 4233-4246
  • 38 Wang TT, Liu Y, Chen L. Synthesis and cytotoxic activity of nitric oxide-releasing isosteviol derivatives. Bioorg Med Chem Lett 2014; 24: 2202-2205
  • 39 Ball MS, Shipman EP, Kim H, Liby KT, Pioli PA. CDDO-Me redirects activation of breast tumor associated macrophages. PLoS One 2016; 11: e0149600
  • 40 Wang YY, Zhe H, Zhao R. Preclinical evidences toward the use of triterpenoid CDDO-Me for solid cancer prevention and treatment. Mol Cancer 2014; 13: 30
  • 41 Gao X, Deeb D, Liu Y, Liu P, Zhang Y, Shaw J, Gautam SC. CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma. Int J Oncol 2015; 47: 2100-2106
  • 42 Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, Sporn MB, Liby KT, Rawal B, Lee JH, Gabrilovich DI. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 2010; 16: 1812-1823
  • 43 Wang YY, Yang YX, Zhe H, He ZX, Zhou SF. Bardoxolone methyl (CDDO-Me) as a therapeutic agent: An update on its pharmacokinetic and pharmacodynamic properties. Drug Des Dev Ther 2014; 8: 2075-2088
  • 44 Cragg GM, Grothaus PG, Newman DJ. New horizons for old drugs and drug leads. J Nat Prod 2014; 77: 703-723
  • 45 Schmid C, Dawid C, Peters V, Hofmann T. Saponins from European licorice roots (Glycyrrhiza glabra). J Nat Prod 2018; 81: 1734-1744
  • 46 Li K, Ji S, Song W, Kuang Y, Lin Y, Tang S, Cui Z, Qiao X, Yu S, Ye M. Glycybridins A–K, bioactive phenolic compounds from Glycyrrhiza glabra . J Nat Prod 2017; 80: 334-346
  • 47 Zhang X, Yang H, Yue S, He G, Qu S, Zhang Z, Ma B, Ding R, Peng W, Zhang H, Yang Z, Dou K, Tao K, Li X. The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma. Cancer Med 2017; 6: 1941-1951
  • 48 Liu SH, Cheng YC. Old formula, new Rx: the journey of PHY906 as cancer adjuvant therapy. J Ethnopharmacol 2012; 140: 614-623
  • 49 Kummar S, Copur MS, Rose M, Wadler S, Stephenson J, OʼRourke M, Brenckman W, Tilton R, Liu SH, Jiang Z, Su T, Cheng YC, Chu E. A phase I study of the Chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Clin Colorect Cancer 2011; 10: 85-96
  • 50 Saif MW, Li J, Lamb L, Kaley K, Elligers K, Jiang Z, Bussom S, Liu SH, Cheng YC. First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 2014; 73: 373-380
  • 51 Ren Y, VanSchoiack A, Chai HB, Goetz M, Kinghorn AD. Cytotoxic barrigenol-like triterpenoids from an extract of Cyrilla racemiflora housed in a repository. J Nat Prod 2015; 78: 2440-2446
  • 52 Jiao Q, Zou L, Liu P, Xu Q, Zhang Y, Yu Y, Zou L, Chi T, Ji X. Xanthoceraside induces apoptosis in melanoma cells through the activation of caspases and the suppression of the IGF-1R/Raf/MEK/ERK signaling pathway. J Med Food 2014; 17: 1070-1078
  • 53 Shanmugam MK, Rajendran P, Li F, Nema T, Vali S, Abbasi T, Kapoor S, Sharma A, Kumar AP, Ho PC, Hui KM, Sethi G. Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice. J Mol Med 2011; 89: 713-727
  • 54 Yang L, Liu X, Lu Z, Chan JYW, Zhou L, Fung KP, Wu P, Wu S. Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor. Cancer Lett 2010; 298: 128-138
  • 55 Zhang J, Wang W, Qian L, Zhang Q, Lai D, Qi C. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition. Oncology Rep 2015; 34: 2375-2384
  • 56 Ren Y, Anaya-Eugenio GD, Czarnecki AA, Ninh TN, Yuan C, Chai HB, Soejarto DD, Burdette JE, Carcache de Blanco EJ, Kinghorn AD. Cytotoxic and NF-κB and mitochondrial transmembrane potential inhibitory pentacyclic triterpenoids from Syzygium corticosum and their semi-synthetic derivatives. Bioorg Med Chem 2018; 26: 4452-4460
  • 57 Hata K, Hori K, Takahashi S. Differentiation- and apoptosis-inducing activities by pentacyclic triterpenes on a mouse melanoma cell line. J Nat Prod 2002; 65: 645-648
  • 58 Tian T, Liu X, Lee ES, Sun J, Feng Z, Zhao L, Zhao C. Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents. Arch Pharm Res 2017; 40: 458-468
  • 59 Sun L, Li B, Su X, Chen G, Li Y, Yu L, Li L, Wei W. An ursolic acid derived small molecule triggers cancer cell death through hyperstimulation of macropinocytosis. J Med Chem 2017; 60: 6638-6648
  • 60 Fan L, Zhang B, Xu A, Shen Z, Guo Y, Zhao R, Yao H, Shao JW. Carrier-free, pure nanodrug formed by the self-assembly of an anticancer drug for cancer immune therapy. Mol Pharm 2018; 15: 2466-2478
  • 61 Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. Ursolic acid inhibits nuclear factor-κB activation induced by carcinogenic agents through suppression of IκBα kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 2003; 63: 4375-4383
  • 62 Qian Z, Wang X, Song Z, Zhang H, Zhou S, Zhao J, Wang H. A phase I trial to evaluate the multiple-dose safety and antitumor activity of ursolic acid liposomes in subjects with advanced solid tumors. Biomed Res Int 2015; 2015: 809714
  • 63 Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX. Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep 2005; 22: 386-399
  • 64 Lee DH, Iwanski GB, Thoennissen NH. Cucurbitacin: Ancient compound shedding new light on cancer treatment. ScientificWorldJournal 2010; 10: 413-418
  • 65 Ríos JL, Andúlar I, Escandell JM, Giner RM, Recio MC. Cucurbitacins as inducers of cell death and a rich source of potential anticancer compounds. Curr Pharm Des 2012; 18: 1663-1676
  • 66 Pan L, Yong Y, Deng Y, Lantvit DD, Ninh TN, Chai H, Carcache de Blanco EJ, Soejarto DD, Swanson SM, Kinghorn AD. Isolation, structure elucidation, and biological evaluation of 16,23-epoxycucurbitacin constituents from Elaeocarpus chinensis . J Nat Prod 2012; 75: 444-452
  • 67 Abbas S, Vincourt JB, Habib L, Netter P, Greige-Gerges H, Magdalou J. The cucurbitacins E, D and I: Investigation of their cytotoxicity toward human chondrosarcoma SW 1353 cell line and their biotransformation in human liver. Toxicol Lett 2013; 216: 189-199
  • 68 Fang X, Phoebe CH, Pezzuto JM, Fong HHS, Farnsworth NR, Yellin B, Hecht SM. Plant anticancer agents. XXXIV. Cucurbitacins from Elaeocarpus dolichostylus . J Nat Prod 1984; 47: 988-993
  • 69 Kim DK, Choi SH, Lee JO, Ryu SY, Park DK, Shin DH, Jung JH, Pyo SK, Lee KR, Zee OP. Cytotoxic constituents of Sorbaria sorbifolia var. stellipila . Arch Pharm Res 1997; 20: 85-87
  • 70 Takahashi N, Yoshida Y, Sugiura T, Matsuno K, Fujino A, Yamashita U. Cucurbitacin D isolated from Trichosanthes kirilowii induces apoptosis in human hepatocellular carcinoma cells in vitro . Int Immunopharmacol 2009; 9: 508-513
  • 71 Spear SA, Burns SS, Oblinger JL, Ren Y, Pan L, Kinghorn AD, Welling DB, Chang LS. Natural compounds as potential treatments of NF2-deficient schwannoma and meningioma: cucurbitacin D and goyazensolide. Otol Neurotol 2013; 34: 1519-1527
  • 72 Ku JM, Kim SR, Hong SH, Choi HS, Seo HS, Shin YC, Ko SG. Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells. Mol Cell Biochem 2015; 409: 33-43
  • 73 Nakanishi T, Song Y, He C, Wang D, Morita K, Tsukada J, Kanazawa T, Yoshida Y. Autophagy is associated with cucurbitacin D-induced apoptosis in human T cell leukemia cells. Med Oncol 2016; 33: 30
  • 74 Hall JA, Seedarala S, Rice N, Kopel L, Halaweish F, Blagg BSJ. Cucurbitacin D is a disruptor of the HSP90 chaperone machinery. J Nat Prod 2015; 78: 873-879
  • 75 Sikander M, Hafeez BB, Malik S, Alsayari A, Halaweish FT, Yallapu MM, Chauhan SC, Jaggi M. Cucurbitacin D exhibits potent anti-cancer activity in cervical cancer. Sci Rep 2016; 6: 36594
  • 76 Ruan J, Zheng C, Qu L, Liu Y, Han L, Yu H, Zhang Y, Wang T. Plant resources, 13C-NMR spectral characteristic and pharmacological activities of dammarane-type triterpenoids. Molecules 2016; 21: 1047
  • 77 Patel S, Rauf A. Adaptogenic herb ginseng (Panax) as medical food: Status quo and future prospects. Biomed Pharmacother 2017; 85: 120-127
  • 78 Chen XJ, Zhang XJ, Shui YM, Wan JB, Gao JL. Anticancer activities of protopanaxadiol- and protopanaxatriol-type ginsenosides and their metabolites. Evid Based Compl Altern Med 2016; 2016: 5738694
  • 79 Wang W, Zhao Y, Rayburn ER, Hill DL, Wang H, Zhang R. In vitro anticancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng . Cancer Chemother Pharmacol 2007; 59: 589-601
  • 80 Kwak JH, Park JY, Lee D, Kwak JY, Park EH, Kim KH, Park HJ, Kim HY, Jang HJ, Ham J, Hwang GS, Yamabe N, Kang KS. Inhibitory effects of ginseng sapogenins on the proliferation of triple negative breast cancer MDA-MB-231 cells. Bioorg Med Chem Lett 2014; 24: 5409-5412
  • 81 Liu GY, Bu X, Yan H, Jia WWG. 20S-Protopanaxadiol-induced programmed cell death in glioma cells through caspase-dependent and -independent pathways. J Nat Prod 2007; 70: 259-264
  • 82 Teng B, Jiang J, Zhao L, Gao J, Chen J, Liu Z, Wang H, Lu B. Ginsenoside PPDʼs antitumor effect via down-regulation of mTOR revealed by super-resolution imaging. Molecules 2017; 22: 486
  • 83 Teng B, Zhao L, Gao J, He P, Li H, Chen J, Feng Q, Yi C. 20(S)-Protopanaxadiol (PPD) increases the radiotherapy sensitivity of laryngeal carcinoma. Food Funct 2017; 8: 4469-4477
  • 84 Zhang Z, Li Z, Wu X, Zhang CF, Calway T, He TC, Du W, Chen J, Wang CZ, Yuan CS. TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol. J Pharmacol Sci 2015; 127: 83-91
  • 85 Wang CZ, Zhang Z, Wan JY, Zhang CF, Anderson S, He X, Yu C, He TC, Qi LW, Yuan CS. Protopanaxadiol, an active ginseng metabolite, significantly enhances the effects of fluorouracil on colon cancer. Nutrients 2015; 7: 799-814
  • 86 Cao B, Qi Y, Yang Y, Liu X, Xu D, Guo W, Zhan Y, Xiong Z, Zhang A, Wang AR, Fu X, Zhang H, Zhao L, Gu J, Dong Y. 20(S)-Protopanaxadiol inhibition of progression and growth of castration-resistant prostate cancer. PLoS One 2014; 9: e111201
  • 87 Zhang B, Zhou WJ, Gu CJ, Wu K, Yang HL, Mei J, Yu JJ, Hou XF, Sun JS, Xu FY, Li DJ, Jin LP, Li MQ. The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity. Cell Death Dis 2018; 9: 574
  • 88 Han M, Ma L, Yu X, Li Z, Guo Y, Wang X. A nanoparticulate drug-delivery system for 20(S)-protopanaxadiol: formulation, characterization, increased oral bioavailability and anti-tumor efficacy. Drug Deliv 2016; 23: 2410-2418
  • 89 Hao M, Wang W, Zhao Y, Zhang R, Wang H. Pharmacokinetics and tissue distribution of 25-hydroxyprotopanaxadiol, an anti-cancer compound isolated from Panax ginseng, in athymic mice bearing xenografts of human pancreatic tumors. Eur J Drug Metab Pharmacokinet 2011; 35: 109-113
  • 90 Bi X, Zhao Y, Fang W, Yang W. Anticancer activity of Panax notoginseng extract 20(S)-25-OCH3-PPD: Targeting β-catenin signaling. Clin Exp Pharmacol Physiol 2009; 36: 1074-1078
  • 91 Wu YL, Wan Y, Jin XJ, OuYang BQ, Bai T, Zhao YQ, Nan JX. 25-OCH3-PPD induces the apoptosis of activated t-HSC/Cl-6 cells via c-FLIP-mediated NF-κB activation. Chem Biol Interact 2011; 194: 106-112
  • 92 Zhao C, Su G, Wang X, Zhang X, Guo S, Zhao Y. Antitumor activity of ginseng sapogenins, 25-OH-PPD and 25-OCH3-PPD, on gastric cancer cells. Biotechnol Lett 2016; 38: 43-50
  • 93 Wang W, Rayburn ER, Zhao Y, Wang H, Zhang R. Novel ginsenosides 25-OH-PPD and 25-OCH3-PPD as experimental therapy for pancreatic cancer: Anticancer activity and mechanisms of action. Cancer Lett 2009; 278: 241-248
  • 94 Li W, Zhang X, Xin Y, Xuan Y, Liu J, Li P, Zhao Y. Oral subchronic toxicity evaluation of a novel antitumor agent 25-methoxydammarane-3,12, 20-triol from Panax notoginseng in Sprague-Dawley rats. Regul Toxicol Pharmacol 2016; 77: 240-251
  • 95 Zhou WX, Sun YY, Yuan WH, Zhao YQ. Water-soluble derivatives of 25-OCH3-PPD and their anti-proliferative activities. Steroids 2017; 121: 32-39
  • 96 Loizzo MR, Menichini F, Tundis R. Recent Insights into the Emerging Role of Triterpenoids in Cancer Therapy: Part I. In: Atta-ur-Rahman. ed. Studies in Natural Products Chemistry, Vol. 40. Amsterdam: Elsevier; 2013: 1-31
  • 97 Tung NH, Song GY, Van Minh C, Van Kiem P, Jin LG, Boo HJ, Kang HK, Kim YH. Steamed ginseng-leaf components enhance cytotoxic effects on human leukemia HL-60 cells. Chem Pharm Bull 2010; 58: 1111-1115
  • 98 Kim JH, Kim M, Yun SM, Lee S, No JH, Suh DH, Kim K, Kim YB. Ginsenoside Rh2 induces apoptosis and inhibits epithelial-mesenchymal transition in HEC1A and Ishikawa endometrial cancer cells. Biomed Pharmacother 2017; 96: 871-876
  • 99 Li KF, Kang CM, Yin XF, Li HX, Chen ZY, Li Y, Zhang Q, Qiu YR. Ginsenoside Rh2 inhibits human A172 glioma cell proliferation and induces cell cycle arrest status via modulating Aκt signaling pathway. Mol Med Rep 2018; 17: 3062-3068
  • 100 Ge G, Yan Y, Cai H. Ginsenoside Rh2 inhibited proliferation by inducing ROS mediated ER stress dependent apoptosis in lung cancer cells. Biol Pharm Bull 2017; 40: 2117-2124
  • 101 Chen Y, Liu ZH, Xia J, Li XP, Li KQ, Xiong W, Li J, Chen DL. 20(S)-ginsenoside Rh2 inhibits the proliferation and induces the apoptosis of KG-1a cells through the Wnt/β-catenin signaling pathway. Oncol Rep 2016; 36: 137-146
  • 102 Lv Q, Rong N, Liu LJ, Xu XL, Liu JT, Jin FX, Wang CM. Antitumoral activity of (20R)- and (20S)-ginsenoside Rh2 on transplanted hepatocellular carcinoma in mice. Planta Med 2016; 82: 705-711
  • 103 Chen F, Sun Y, Zheng SL, Qin Y, McClements DJ, Hu JN, Deng ZY. Antitumor and immunomodulatory effects of ginsenoside Rh2 and its octyl ester derivative in H22 tumor-bearing mice. J Funct Foods 2017; 32: 382-390
  • 104 Li Q, Li B, Dong C, Wang Y, Li Q. 20(S)-Ginsenoside Rh2 suppresses proliferation and migration of hepatocellular carcinoma cells by targeting EZH2 to regulate CDKN2A-2B gene cluster transcription. Eur J Pharmacol 2017; 815: 173-180
  • 105 Wang YS, Lin Y, Li H, Li Y, Song Z, Jin YH. The identification of molecular target of (20S)-ginsenoside Rh2 for its anti-cancer activity. Sci Rep 2017; 7: 12408
  • 106 Wang M, Yan SJ, Zhang HT, Li N, Liu T, Zhang YL, Li XX, Ma Q, Qiu XC, Fan QY, Ma BA. Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model. Oncol Lett 2017; 13: 681-685
  • 107 Achenbach H, Asunka SA, Weibel R, Addae-Mensah I, Oppong IV. Dichapetalin A, a novel plant constituent from Dichapetalum madagascariense with potential antineoplastic activity. Nat Prod Lett 1995; 7: 93-100
  • 108 Tuchinda P, Kornsakulkarn J, Pohmakotr M, Kongsaeree P, Prabpai S, Yoosook C, Kasisit J, Napaswad C, Sophasan S, Reutrakul V. Dichapetalin-type triterpenoids and lignans from the aerial parts of Phyllanthus acutissima . J Nat Prod 2008; 71: 655-663
  • 109 Fang L, Ito A, Chai HB, Mi Q, Jones WP, Madulid DR, Oliveros MB, Gao Q, Orjala J, Farnsworth NR, Soejarto DD, Cordell GA, Swanson SM, Pezzuto JM, Kinghorn AD. Cytotoxic constituents from the stem bark of Dichapetalum gelonioides collected in the Philippines. J Nat Prod 2006; 69: 332-337
  • 110 Ren Y, Yuan C, Deng Y, Kanagasabai R, Ninh TN, Tu VT, Chai HB, Soejarto DD, Fuchs JR, Yalowich JC, Yu J, Kinghorn AD. Cytotoxic and natural killer cell stimulatory constituents of Phyllanthus songboiensis . Phytochemistry 2015; 111: 132-140
  • 111 Shanmugam MK, Dai X, Kumar AP, Tan BKH, Sethi G, Bishayee A. Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies. Biochem Pharmacol 2013; 85: 1579-1587
  • 112 Safe SH, Prather PL, Brents LK, Chadalapaka G, Jutooru I. Unifying mechanisms of action of the anticancer activities of triterpenoids and synthetic analogs. Anticancer Agents Med Chem 2012; 12: 1211-1220
  • 113 Ren Y, Yu J, Kinghorn AD. Development of anticancer agents from plant-derived sesquiterpene lactones. Curr Med Chem 2016; 23: 2397-2420