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Mechanism of Action of the Anti-cancer Agent, Triptolide

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Nutraceuticals and Cancer

Abstract

Triptolide, a dipertene triepoxide isolated from the roots of the Chinese herb Tripterygium wilfordii Hook F., is a promising anti-cancer agent. While its role as a promoter of cell death, both in vivo and in vitro, in various cancers is well established, the mechanism by which it induces cell death in cancer cells is not well understood, and has therefore been the subject of intense interest in the past decade. Studies to date have shown that triptolide acts in a pleiotropic fashion, resulting in decrease of HSP70 expression, affecting calcium release, causing lysosomal membrane depolarization, inhibiting NFκB activity, iNOS and Cox-2 expression, as well as acting as a transcription inhibitor and an anti-angiogenesis factor. In this review, we discuss the possible modes of action of triptolide in various cancers, as well as a novel compound derived from triptolide currently being prepared for Phase I clinical trials.

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References

  • Aghdassi A, Phillips P, Dudeja V, Dhaulakhandi D, Sharif R, Dawra R, Lerch MM, Saluja A (2007) Heat shock protein 70 increases tumorigenicity and inhibits apoptosis in pancreatic adenocarcinoma. Cancer Res 67(2):616–625

    Article  PubMed  CAS  Google Scholar 

  • Ahn B, Ohshima H (2001) Suppression of intestinal polyposis in Apc(Min/+) mice by inhibiting nitric oxide production. Cancer Res 61(23):8357–8360

    PubMed  CAS  Google Scholar 

  • Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357(Pt 3):593–615

    Article  PubMed  CAS  Google Scholar 

  • Antonoff MB, Chugh R, Borja-Cacho D, Dudeja V, Clawson KA, Skube SJ, Sorenson BS, Saltzman DA, Vickers SM, Saluja AK (2009) Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. Surgery 146(2):282–290

    Article  PubMed  Google Scholar 

  • Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545

    Article  PubMed  CAS  Google Scholar 

  • Bao X, Cui J, Wu Y, Han X, Gao C, Hua Z, Shen P (2007) The roles of endogenous reactive oxygen species and nitric oxide in triptolide-induced apoptotic cell death in macrophages. J Mol Med 85(1):85–98

    Article  PubMed  CAS  Google Scholar 

  • Borja-Cacho D, Yokoyama Y, Chugh RK, Mujumdar NR, Dudeja V, Clawson KA, Dawra RK, Saluja AK, Vickers SM (2010) TRAIL and triptolide: an effective combination that induces apoptosis in pancreatic cancer cells. J Gastrointest Surg 14(2):252–260

    Article  PubMed  Google Scholar 

  • Bursch W, Ellinger A, Gerner C, Frohwein U, Schulte-Hermann R (2000) Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Ann N Y Acad Sci 926:1–12

    Article  PubMed  CAS  Google Scholar 

  • Carter BZ, Mak DH, Schober WD, McQueen T, Harris D, Estrov Z, Evans RL, Andreeff M (2006) Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells. Blood 108(2):630–637

    Article  PubMed  CAS  Google Scholar 

  • Carter BZ, Mak DH, Schober WD, Dietrich MF, Pinilla C, Vassilev LT, Reed JC, Andreeff M (2008) Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5. Blood 111(7):3742–3750

    Article  PubMed  CAS  Google Scholar 

  • Chiou WF, Chou CJ, Chen CF (2001) Camptothecin suppresses nitric oxide biosynthesis in RAW 264.7 macrophages. Life Sci 69(6):625–635

    Article  PubMed  CAS  Google Scholar 

  • Clawson KA, Borja-Cacho D, Antonoff MB, Saluja AK, Vickers SM (2010) Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinoma. J Surg Res 163(2):244–249

    Article  PubMed  CAS  Google Scholar 

  • Csiki I, Morrow JD, Sandler A, Shyr Y, Oates J, Williams MK, Dang T, Carbone DP, Johnson DH (2005) Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Cancer Res 11(18):6634–6640

    Article  PubMed  CAS  Google Scholar 

  • Dai YQ, Jin DZ, Zhu XZ, Lei DL (2006) Triptolide inhibits COX-2 expression via NF-kappa B pathway in astrocytes. Neurosci Res 55(2):154–160

    Article  PubMed  CAS  Google Scholar 

  • Dudeja V, Mujumdar N, Phillips P, Chugh R, Borja-Cacho D, Dawra RK, Vickers SM, Saluja AK (2009) Heat shock protein70 inhibits apoptosis in cancer cells through simultaneous and independent mechanisms. Gastroenterology 136(5):1772–1782

    Google Scholar 

  • Dudeja V, Chugh RK, Sangwan V, Skube SJ, Mujumdar NR, Antonoff MB, Dawra RK, Vickers SM, Saluja AK (2011) Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors. Am J Physiol Gastrointest Liver Physiol 300(6):G948–955

    Article  PubMed  CAS  Google Scholar 

  • Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998

    Article  PubMed  CAS  Google Scholar 

  • Ferrari V, Valcamonico F, Amoroso V, Simoncini E, Vassalli L, Marpicati P, Rangoni G, Grisanti S, Tiberio GA, Nodari F, Strina C, Marini G (2006) Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol 57(2):185–190

    Article  PubMed  CAS  Google Scholar 

  • Fidler JM, Li K, Chung C, Wei K, Ross JA, Gao M, Rosen GD (2003) PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy. Mol Cancer Ther 2(9):855–862

    PubMed  CAS  Google Scholar 

  • Garcia-Becerra R, Borja-Cacho E, Cooney AJ, Smith CL, Lemus AE, Perez-Palacios G, Larrea F (2006) Synthetic 19-nortestosterone derivatives as estrogen receptor alpha subtype-selective ligands induce similar receptor conformational changes and steroid receptor coactivator recruitment than natural estrogens. J Steroid Biochem Mol Biol 99(2–3):108–114

    Article  PubMed  CAS  Google Scholar 

  • Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5(22):2592–2601

    Article  PubMed  CAS  Google Scholar 

  • Gasparini G, Gattuso D, Morabito A, Longo R, Torino F, Sarmiento R, Vitale S, Gamucci T, Mariani L (2005a) Combined therapy with weekly irinotecan, infusional 5-fluorouracil and the selective COX-2 inhibitor rofecoxib is a safe and effective second-line treatment in metastatic colorectal cancer. Oncologist 10(9):710–717

    Article  PubMed  CAS  Google Scholar 

  • Gasparini G, Meo S, Comella G, Stani SC, Mariani L, Gamucci T, Avallone A, Lo Vullo S, Mansueto G, Bonginelli P, Gattuso D, Gion M (2005b) The combination of the selective cyclooxygenase-2 inhibitor celecoxib with weekly paclitaxel is a safe and active second-line therapy for non-small cell lung cancer: A phase II study with biological correlates. Cancer J 11(3):209–216

    Article  PubMed  CAS  Google Scholar 

  • Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  PubMed  CAS  Google Scholar 

  • Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ (2000) Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60(19):5334–5339

    PubMed  CAS  Google Scholar 

  • Jiang XH, Wong BC, Lin MC, Zhu GH, Kung HF, Jiang SH, Yang D, Lam SK (2001) Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene 20(55):8009–8018

    Article  PubMed  CAS  Google Scholar 

  • Johnson SM, Wang X, Mark Evers B (2011) Triptolide inhibits proliferation and migration of colon cancer cells by inhibition of cell cycle regulators and cytokine receptors. J Surg Res 168(2):197–205

    Google Scholar 

  • Joo M, Chi JG, Lee H (2005) Expressions of HSP70 and HSP27 in hepatocellular carcinoma. J Korean Med Sci 20(5):829–834

    Article  PubMed  CAS  Google Scholar 

  • Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3(3):221–227

    Article  PubMed  CAS  Google Scholar 

  • Kim YH, Lee SH, Lee JY, Choi SW, Park JW, Kwon TK (2004) Triptolide inhibits murine-inducible nitric oxide synthase expression by down-regulating lipopolysaccharide-induced activity of nuclear factor-kappa B and c-Jun NH2-terminal kinase. Eur J Pharmacol 494(1):1–9

    Article  PubMed  CAS  Google Scholar 

  • Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721

    Article  PubMed  CAS  Google Scholar 

  • Ko JK, Leung WC, Ho WK, Chiu P (2007) Herbal diterpenoids induce growth arrest and apoptosis in colon cancer cells with increased expression of the nonsteroidal anti-inflammatory drug-activated gene. Eur J Pharmacol 559(1):1–13

    Article  PubMed  CAS  Google Scholar 

  • Lee KY, Chang W, Qiu D, Kao PN, Rosen GD (1999) PG490 (triptolide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells. J Biol Chem 274(19):13451–13455

    Article  PubMed  CAS  Google Scholar 

  • Lee KY, Park JS, Jee YK, Rosen GD (2002) Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-kappaB activation. Exp Mol Med 34(6):462–468

    PubMed  CAS  Google Scholar 

  • Leuenroth SJ, Crews CM (2005) Studies on calcium dependence reveal multiple modes of action for triptolide. Chem Biol 12(12):1259–1268

    Article  PubMed  CAS  Google Scholar 

  • Leuenroth SJ, Crews CM (2008) Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure. Cancer Res 68(13):5257–5266

    Article  PubMed  CAS  Google Scholar 

  • Li H, Sui C, Kong F, Zhang H, Liu J, Dong M (2007) Expression of HSP70 and JNK-related proteins in human liver cancer: Potential effects on clinical outcome. Dig Liver Dis 39(7):663–670

    Article  PubMed  CAS  Google Scholar 

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489

    Article  PubMed  CAS  Google Scholar 

  • Liu RH, Hotchkiss JH (1995) Potential genotoxicity of chronically elevated nitric oxide: a review. Mutat Res 339(2):73–89

    PubMed  CAS  Google Scholar 

  • Liu J, Wu QL, Feng YH, Wang YF, Li XY, Zuo JP (2005) Triptolide suppresses CD80 and CD86 expressions and IL-12 production in THP-1 cells. Acta Pharmacol Sin 26(2):223–227

    Article  PubMed  CAS  Google Scholar 

  • Luzio JP, Pryor PR, Bright NA (2007) Lysosomes: fusion and function. Nat Rev Mol Cell Biol 8(8):622–632

    Article  PubMed  CAS  Google Scholar 

  • MacMicking J, Xie QW, Nathan C (1997) Nitric oxide and macrophage function. Annu Rev Immunol 15:323–350

    Article  PubMed  CAS  Google Scholar 

  • Marks-Konczalik J, Chu SC, Moss J (1998) Cytokine-mediated transcriptional induction of the human inducible nitric oxide synthase gene requires both activator protein 1 and nuclear factor kappaB-binding sites. J Biol Chem 273(35):22201–22208

    Article  PubMed  CAS  Google Scholar 

  • Martin E, Nathan C, Xie QW (1994) Role of interferon regulatory factor 1 in induction of nitric oxide synthase. J Exp Med 180(3):977–984

    Article  PubMed  CAS  Google Scholar 

  • McCallum C, Kwon S, Leavitt P, Shen DM, Liu W, Gurnett A (2007) Triptolide binds covalently to a 90 kDa nuclear protein. Role of epoxides in binding and activity. Immunobiology 212(7):549–556

    Article  PubMed  CAS  Google Scholar 

  • Messina ME, Jr., Halaby R (2011) Does triptolide induce lysosomal-mediated apoptosis in human breast cancer cells? Med Hypotheses 77(1):91–93

    Article  PubMed  CAS  Google Scholar 

  • Moncada C, Arvin B, Le Peillet E, Meldrum BS (1991a) Non-NMDA antagonists protect against kainate more than AMPA toxicity in the rat hippocampus. Neurosci Lett 133(2):287–290

    Article  PubMed  CAS  Google Scholar 

  • Moncada S, Palmer RM, Higgs EA (1991b) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43(2):109–142

    PubMed  CAS  Google Scholar 

  • Monteith GR, McAndrew D, Faddy HM, Roberts-Thomson SJ (2007) Calcium and cancer: targeting Ca2+ transport. Nat Rev Cancer 7(7):519–530

    Article  PubMed  CAS  Google Scholar 

  • Mujumdar N, Mackenzie T, Dudeja V, Chugh R, Antonoff M, Borja-Cacho D, Sangwan V, Dawra R, Vickers SM, Saluja AK (2010) Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways. Gastroenterology 139(2):598–608

    Google Scholar 

  • Muller AJ, Scherle PA (2006) Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer 6(8):613–625

    Article  PubMed  CAS  Google Scholar 

  • Nathan C, Xie QW (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269(19):13725–13728

    PubMed  CAS  Google Scholar 

  • Nugent FW, Mertens WC, Graziano S, Levitan N, Collea R, Gajra A, Marshall J, McCann J (2005) Docetaxel and cyclooxygenase-2 inhibition with celecoxib for advanced non-small cell lung cancer progressing after platinum-based chemotherapy: a multicenter phase II trial. Lung Cancer 48(2):267–273

    Article  PubMed  Google Scholar 

  • Ohmori Y, Hamilton TA (2001) Requirement for STAT1 in LPS-induced gene expression in macrophages. J Leukoc Biol 69(4):598–604

    PubMed  CAS  Google Scholar 

  • Pereg D, Lishner M (2005) Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer. J Intern Med 258(2):115–123

    Article  PubMed  CAS  Google Scholar 

  • Phillips PA, Dudeja V, McCarroll JA, Borja-Cacho D, Dawra RK, Grizzle WE, Vickers SM, Saluja AK (2007) Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res 67(19):9407–9416

    Article  PubMed  CAS  Google Scholar 

  • Shamon LA, Pezzuto JM, Graves JM, Mehta RR, Wangcharoentrakul S, Sangsuwan R, Chaichana S, Tuchinda P, Cleason P, Reutrakul V (1997) Evaluation of the mutagenic, cytotoxic, and antitumor potential of triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii. Cancer Lett 112(1):113–117

    Article  PubMed  Google Scholar 

  • Sherman M, Multhoff G (2007) Heat shock proteins in cancer. Ann N Y Acad Sci 1113:192–201

    Article  PubMed  CAS  Google Scholar 

  • Tao X, Schulze-Koops H, Ma L, Cai J, Mao Y, Lipsky PE (1998) Effects of Tripterygium wilfordii hook F extracts on induction of cyclooxygenase 2 activity and prostaglandin E2 production. Arthritis Rheum 41(1):130–138

    Article  PubMed  CAS  Google Scholar 

  • Taylor BS, Alarcon LH, Billiar TR (1998) Inducible nitric oxide synthase in the liver: regulation and function. Biochemistry (Mosc) 63(7):766–781

    CAS  Google Scholar 

  • Vispe S, DeVries L, Creancier L, Besse J, Breand S, Hobson DJ, Svejstrup JQ, Annereau JP, Cussac D, Dumontet C, Guilbaud N, Barret JM, Bailly C (2009) Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA. Mol Cancer Ther 8(10):2780–2790

    Article  PubMed  CAS  Google Scholar 

  • Wang CY, Cusack JC, Jr., Liu R, Baldwin AS, Jr (1999) Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med 5(4):412–417

    Article  PubMed  Google Scholar 

  • Wang X, Matta R, Shen G, Nelin LD, Pei D, Liu Y (2006) Mechanism of triptolide-induced apoptosis: Effect on caspase activation and Bid cleavage and essentiality of the hydroxyl group of triptolide. J Mol Med 84(5):405–415

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Jin H, Xu R, Mei Q, Fan D (2009) Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp Mol Med 41(10):717–727

    Article  PubMed  CAS  Google Scholar 

  • Westerheide SD, Kawahara TL, Orton K, Morimoto RI (2006) Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem 281(14):9616–9622

    Article  PubMed  CAS  Google Scholar 

  • Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269(7):4705–4708

    PubMed  CAS  Google Scholar 

  • Yang S, Chen J, Guo Z, Xu XM, Wang L, Pei XF, Yang J, Underhill CB, Zhang L (2003) Triptolide inhibits the growth and metastasis of solid tumors. Mol Cancer Ther 2(1):65–72

    PubMed  CAS  Google Scholar 

  • Yang SW, Wang W, Xie XY, Zhu WP, Li FQ (2011) In vitro synergistic cytotoxic effect of triptolide combined with hydroxycamptothecin on pancreatic cancer cells. Am J Chin Med 39(1):121–134

    Article  PubMed  Google Scholar 

  • Yao H, Zhou J, Li D, Wu N, Bader A, Hoxtermann S, Altmeyer P, Brockmeyer NH (2005) FK506 enhances triptolide-induced down-regulation of cyclooxygenase-2, inducible nitric oxide synthase as well as their products PGE2 and NO in TNF-alpha-stimulated synovial fibroblasts from rheumatoid arthritic patients. Eur J Med Res 10(3):110–116

    PubMed  CAS  Google Scholar 

  • Yinjun L, Jie J, Yungui W (2005) Triptolide inhibits transcription factor NF-kappaB and induces apoptosis of multiple myeloma cells. Leuk Res 29(1):99–105

    Article  PubMed  Google Scholar 

  • Zhou HF, Liu XY, Niu DB, Li FQ, He QH, Wang XM (2005) Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection. Neurobiol Dis 18(3):441–449

    Article  PubMed  CAS  Google Scholar 

  • Zhou R, Zheng SX, Tang W, He PL, Li XY, Yang YF, Li YC, Geng JG, Zuo JP (2006) Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide in interferon-gamma- and bacterial lipopolysaccharide-stimulated macrophages. J Pharmacol Exp Ther 316(1):121–128

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Surgery, University of Minnesota, Minneapolis, MN, USA

    Veena Sangwan & Ashok K. Saluja

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  1. Veena Sangwan
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  2. Ashok K. Saluja
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Correspondence to Ashok K. Saluja .

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  1. , Barbara Ann Karmanos Cancer Institute, Department of Pathology, John R Street, Detroit, 48201, USA

    Fazlul H. Sarkar

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Sangwan, V., Saluja, A.K. (2012). Mechanism of Action of the Anti-cancer Agent, Triptolide. In: Sarkar, F. (eds) Nutraceuticals and Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2630-7_7

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