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Current Stem Cell Research & Therapy

Author(s): Youhan Wang*, Biao Wang* and Xiaobin Yang*

DOI: 10.2174/1574888X14666190301155810

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The Study of Cellular Mechanism of Triptolide in the Treatment of Cancer, Bone Loss and Cardiovascular Disease and Triptolide’s Toxicity

Page: [18 - 23] Pages: 6

  • * (Excluding Mailing and Handling)

Abstract

Triptolide (TPL), the active component of Tripterygium wilfordii Hook F (Twhf) has been used to treat cancer and bone loss conditions for over two hundred years in traditional Chinese medicine (TCM). In this paper, we reviewed the specific molecular mechanisms in the treatment of cancer, bone loss and cardiovascular disease. In addition, we analyze the toxicity of TPL and collect some optimized derivatives extracted from TPL. Although positive results were obtained in most cell culture and animal studies, further studies are needed to substantiate the beneficial effects of TPL.

Keywords: Triptolide, bone loss, anti-cancer, cardiovascular disease, toxicity, cancer.

[1]
Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: A double-blind, placebo-controlled study. Arthritis Rheum 2002; 46(7): 1735-43.
[http://dx.doi.org/10.1002/art.10411] [PMID: 12124856]
[2]
Tao X, Lipsky PE. The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. Rheum Dis Clin North Am 2000; 26(1): 29-50, viii. [viii.].
[http://dx.doi.org/10.1016/S0889-857X(05)70118-6] [PMID: 10680192]
[3]
Han R, Rostami-Yazdi M, Gerdes S, Mrowietz U. Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases. Br J Clin Pharmacol 2012; 74(3): 424-36.
[http://dx.doi.org/10.1111/j.1365-2125.2012.04221.x] [PMID: 22348323]
[4]
Liacini A, Sylvester J, Zafarullah M. Triptolide suppresses proinflammatory cytokine-induced matrix metalloproteinase and aggrecanase-1 gene expression in chondrocytes. Biochem Biophys Res Commun 2005; 327(1): 320-7.
[http://dx.doi.org/10.1016/j.bbrc.2004.12.020] [PMID: 15629465]
[5]
Ziaei S, Halaby R. Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review. Avicenna J Phytomed 2016; 6(2): 149-64.
[PMID: 27222828]
[6]
Zhang Q, Li Y, Liu M, Duan J, Zhou X, Zhu H. Compatibility with panax notoginseng and rehmannia glutinosa alleviates the hepatotoxicity and nephrotoxicity of tripterygium wilfordii via modulating the pharmacokinetics of triptolide. Int J Mol Sci 2018; 19(1)E305
[http://dx.doi.org/10.3390/ijms19010305] [PMID: 29351251]
[7]
Wen HL, Liang ZS, Zhang R, Yang K. Anti-inflammatory effects of triptolide improve left ventricular function in a rat model of diabetic cardiomyopathy. Cardiovasc Diabetol 2013; 12: 50.
[http://dx.doi.org/10.1186/1475-2840-12-50] [PMID: 23530831]
[8]
Phillips PA, Dudeja V, McCarroll JA, et al. Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res 2007; 67(19): 9407-16.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1077] [PMID: 17909050]
[9]
Johnson SM, Wang X, Evers BM. Triptolide inhibits proliferation and migration of colon cancer cells by inhibition of cell cycle regulators and cytokine receptors. J Surg Res 2011; 168(2): 197-205.
[http://dx.doi.org/10.1016/j.jss.2009.07.002] [PMID: 19922946]
[10]
MacKenzie TN, Mujumdar N, Banerjee S, et al. Triptolide induces the expression of miR-142-3p: A negative regulator of heat shock protein 70 and pancreatic cancer cell proliferation. Mol Cancer Ther 2013; 12(7): 1266-75.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-1231] [PMID: 23635652]
[11]
Villicaña C, Cruz G, Zurita M. The genetic depletion or the triptolide inhibition of TFIIH in p53-deficient cells induces a JNK-dependent cell death in Drosophila. J Cell Sci 2013; 126(Pt 11): 2502-15.
[http://dx.doi.org/10.1242/jcs.122721] [PMID: 23549790]
[12]
Lu N, Liu J, Liu J, et al. Antagonist effect of triptolide on AKT activation by truncated retinoid X receptor-alpha. PLoS One 2012; 7(4)e35722
[http://dx.doi.org/10.1371/journal.pone.0035722] [PMID: 22545132]
[13]
Mujumdar N, Mackenzie TN, Dudeja V, et al. Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways. Gastroenterology 2010; 139(2): 598-608.
[http://dx.doi.org/10.1053/j.gastro.2010.04.046] [PMID: 20434451]
[14]
Antonoff MB, Chugh R, Borja-Cacho D, et al. Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. Surgery 2009; 146(2): 282-90.
[http://dx.doi.org/10.1016/j.surg.2009.04.023] [PMID: 19628086]
[15]
Yang Y, Zhang LJ, Bai XG, Xu HJ, Jin ZL, Ding M. Synergistic antitumour effects of triptolide plus gemcitabine in bladder cancer. Biomed Pharmacothera = Biomedecine & Pharmacotherapie 2018; 106: 1307-16.
[16]
Jiang XH, Wong BC, Lin MC, et al. Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene 2001; 20(55): 8009-18.
[http://dx.doi.org/10.1038/sj.onc.1204981] [PMID: 11753684]
[17]
Wang X, Feng Z, Li J, Chen L, Tang W. High glucose induces autophagy of MC3T3-E1 cells via ROS-AKT-mTOR axis. Mol Cell Endocrinol 2016; 429: 62-72.
[http://dx.doi.org/10.1016/j.mce.2016.03.036] [PMID: 27068641]
[18]
Park SJ, Ryu J, Kim IH, Choi YH, Nam TJ. Activation of the mTOR signaling pathway in breast cancer MCF-7 cells by a peptide derived from Porphyra yezoensis. Oncol Rep 2015; 33(1): 19-24.
[http://dx.doi.org/10.3892/or.2014.3557] [PMID: 25333576]
[19]
Qin G, Li P, Xue Z. Triptolide induces protective autophagy and apoptosis in human cervical cancer cells by downregulating Akt/mTOR activation. Oncol Lett 2018; 16(3): 3929-34.
[http://dx.doi.org/10.3892/ol.2018.9074] [PMID: 30128010]
[20]
Carter BZ, Gronda M, Wang Z, et al. Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells. Blood 2005; 105(10): 4043-50.
[http://dx.doi.org/10.1182/blood-2004-08-3168] [PMID: 15687241]
[21]
Wei B, Huang Q, Huang S, Mai W, Zhong X. Trichosanthin-induced autophagy in gastric cancer cell MKN-45 is dependent on reactive oxygen species (ROS) and NF-κB/p53 pathway. J Pharmacol Sci 2016; 131(2): 77-83.
[http://dx.doi.org/10.1016/j.jphs.2016.03.001] [PMID: 27032906]
[22]
Rubinstein AD, Kimchi A. Life in the balance - a mechanistic view of the crosstalk between autophagy and apoptosis. J Cell Sci 2012; 125(Pt 22): 5259-68.
[http://dx.doi.org/10.1242/jcs.115865] [PMID: 23377657]
[23]
Lee KY, Chang W, Qiu D, Kao PN, Rosen GD. PG490 (triptolide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells. J Biol Chem 1999; 274(19): 13451-5.
[http://dx.doi.org/10.1074/jbc.274.19.13451] [PMID: 10224110]
[24]
Tang XY, Zhu YQ, Tao WH, Wei B, Lin XL. Synergistic effect of triptolide combined with 5-fluorouracil on colon carcinoma. Postgrad Med J 2007; 83(979): 338-43.
[http://dx.doi.org/10.1136/pgmj.2006.055426] [PMID: 17488865]
[25]
Lin Y, Yang X, Lu M, et al. Herbal compound triptolide synergistically enhanced antitumor activity of vasostatin120-180. Anticancer Drugs 2013; 24(9): 945-57.
[http://dx.doi.org/10.1097/CAD.0b013e3283651862] [PMID: 23958791]
[26]
Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289(5484): 1504-8.
[http://dx.doi.org/10.1126/science.289.5484.1504] [PMID: 10968780]
[27]
Geusens P. The role of RANK ligand/osteoprotegerin in rheumatoid arthritis. Ther Adv Musculoskelet Dis 2012; 4(4): 225-33.
[http://dx.doi.org/10.1177/1759720X12438080] [PMID: 22859921]
[28]
Luo D, Ren H, Zhang H, et al. The protective effects of triptolide on age-related bone loss in old male rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 98: 280-5.
[29]
Liu C, Zhang Y, Kong X, et al. Triptolide prevents bone destruction in the collagen-induced arthritis model of rheumatoid arthritis by targeting RANKL/RANK/OPG signal pathway. eCAM 2013; 2013: 626038.
[30]
Huang J, Zhou L, Wu H, et al. Triptolide inhibits osteoclast formation, bone resorption, RANKL-mediated NF-қB activation and titanium particle-induced osteolysis in a mouse model. Mol Cell Endocrinol 2015; 399: 346-53.
[http://dx.doi.org/10.1016/j.mce.2014.10.016] [PMID: 25448849]
[31]
Chang WT, Kang JJ, Lee KY, et al. Triptolide and chemotherapy cooperate in tumor cell apoptosis: A role for the p53 pathway. J Biol Chem 2001; 276(3): 2221-7.
[http://dx.doi.org/10.1074/jbc.M009713200] [PMID: 11053449]
[32]
Park B. Triptolide, a diterpene, inhibits osteoclastogenesis, induced by RANKL signaling and human cancer cells. Biochimie 2014; 105: 129-36.
[http://dx.doi.org/10.1016/j.biochi.2014.07.003] [PMID: 25047443]
[33]
Al-Khazraji BK, Appleton CT, Beier F, Birmingham TB, Shoemaker JK. Osteoarthritis, cerebrovascular dysfunction and the common denominator of inflammation: A narrative review. Osteoarthritis Cartilage 2018; 26(4): 462-70.
[http://dx.doi.org/10.1016/j.joca.2018.01.011] [PMID: 29406252]
[34]
Qian K, Zhang L, Shi K. Triptolide prevents osteoarthritis via inhibiting hsa-miR-20b. Inflammopharmacology 2018; 27(1): 109-19.
[PMID: 29974310]
[35]
Collison J. Rheumatoid arthritis: Tipping the balance towards resolution. Nat Rev Rheumatol 2016; 12(11): 622.
[http://dx.doi.org/10.1038/nrrheum.2016.159] [PMID: 27652507 ]
[36]
Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken) 2012; 64(5): 640-7.
[http://dx.doi.org/10.1002/acr.21649] [PMID: 22473918]
[37]
Mullen MB, Saag KG. Evaluating and mitigating fracture risk in established rheumatoid arthritis. Best Pract Res Clin Rheumatol 2015; 29(4-5): 614-27.
[http://dx.doi.org/10.1016/j.berh.2015.09.005] [PMID: 26697770]
[38]
Wright HL, Cross AL, Edwards SW, Moots RJ. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford) 2014; 53(7): 1321-31.
[http://dx.doi.org/10.1093/rheumatology/keu035] [PMID: 24609058]
[39]
Wright HL, Moots RJ, Bucknall RC, Edwards SW. Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 2010; 49(9): 1618-31.
[http://dx.doi.org/10.1093/rheumatology/keq045] [PMID: 20338884]
[40]
Zhang S, Huang G, Yuan K, et al. Tanshinone IIA ameliorates chronic arthritis in mice by modulating neutrophil activities. Clin Exp Immunol 2017; 190(1): 29-39.
[http://dx.doi.org/10.1111/cei.12993] [PMID: 28542869]
[41]
Huang G, Yuan K, Zhu Q, et al. Triptolide inhibits the inflammatory activities of neutrophils to ameliorate chronic arthritis. Mol Immunol 2018; 101: 210-20.
[http://dx.doi.org/10.1016/j.molimm.2018.06.012] [PMID: 30007231]
[42]
Mancino AT, Klimberg VS, Yamamoto M, Manolagas SC, Abe E. Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. J Surg Res 2001; 100(1): 18-24.
[http://dx.doi.org/10.1006/jsre.2001.6204] [PMID: 11516200]
[43]
Zhao X, Sun X, Gao F, Luo J, Sun Z. Effects of ulinastatin and docataxel on breast tumor growth and expression of IL-6, IL-8, and TNF-alpha. J Exp Clin Cancer Res 2011; 30(1): 22.
[44]
Wang S, Zuo S, Liu Z, Ji X, Yao Z, Wang X. Study on the efficacy and mechanism of triptolide on treating TNF transgenic mice with rheumatoid arthritis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 106: 813-20.
[45]
Li N, Ma T, Han J, et al. Increased apoptosis induction in CD4+ CD25+ Foxp3+ T cells contributes to enhanced disease activity in patients with rheumatoid arthritis through IL-10 regulation. Eur Rev Med Pharmacol Sci 2014; 18(1): 78-85.
[PMID: 24452947]
[46]
Xu H, Zhao H, Lu C, et al. Triptolide inhibits osteoclast differentiation and bone resorption in vitro via enhancing the production of IL-10 and TGF-β1 by regulatory T cells. Mediators Inflamm 2016; 20168048170
[http://dx.doi.org/10.1155/2016/8048170] [PMID: 27413257]
[47]
Wang Y, Guo SH, Shang XJ, et al. Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response. Acta Pharmacol Sin 2018; 39(2): 311-27.
[http://dx.doi.org/10.1038/aps.2017.95] [PMID: 28905938]
[48]
Tao R, Lu L, Zhang R, Hu J, Ni J, Shen W. Triptolide inhibits rat vascular smooth muscle cell proliferation and cell cycle progression via attenuation of ERK1/2 and Rb phosphorylation. Exp Mol Pathol 2011; 90(2): 137-42.
[http://dx.doi.org/10.1016/j.yexmp.2010.12.001] [PMID: 21167829]
[49]
Li G, Ren J, Wang G, et al. T2 enhances in situ level of Foxp3+ regulatory cells and modulates inflammatory cytokines in Crohn’s disease. Int Immunopharmacol 2014; 18(2): 244-8.
[http://dx.doi.org/10.1016/j.intimp.2013.12.014] [PMID: 24369313]
[50]
Li J, Jin J, Li M, et al. Role of Nrf2 in protection against triptolide-induced toxicity in rat kidney cells. Toxicol Lett 2012; 213(2): 194-202.
[http://dx.doi.org/10.1016/j.toxlet.2012.07.008] [PMID: 22820427]
[51]
Sun L, Li H, Huang X, et al. Triptolide alters barrier function in renal proximal tubular cells in rats. Toxicol Lett 2013; 223(1): 96-102.
[http://dx.doi.org/10.1016/j.toxlet.2013.08.014] [PMID: 24008046]
[52]
Meng YK, Li CY, Li RY, et al. Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPAR-γ. Acta Pharmacol Sin 2017; 38(10): 1340-52.
[http://dx.doi.org/10.1038/aps.2017.32] [PMID: 28649126 ]
[53]
Xaus J, Comalada M, Valledor AF, et al. LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha. Blood 2000; 95(12): 3823-31.
[http://dx.doi.org/10.1182/blood.V95.12.3823.012k07_3823_3831] [PMID: 10845916]
[54]
Zhang J, Liu L, Mu X, Jiang Z, Zhang L. Effect of triptolide on estradiol release from cultured rat granulosa cells. Endocr J 2012; 59(6): 473-81.
[http://dx.doi.org/10.1507/endocrj.EJ11-0407] [PMID: 22447140]
[55]
Chugh R, Sangwan V, Patil SP, et al. A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer. Sci Transl Med 2012; 4(156)156ra139
[http://dx.doi.org/10.1126/scitranslmed.3004334] [PMID: 23076356]
[56]
Wang X, Sun H, Chen G, et al. Immunosuppression with a combination of pg490-88 and a subtherapeutic dose of FK506 in a canine renal allograft model. Transplantation 2005; 79(11): 1537-44.
[http://dx.doi.org/10.1097/01.TP.0000159149.07292.2B] [PMID: 15940043]
[57]
Pan F, Fisniku O, Wynn C, et al. PG490-88, a new immunosuppressant, effectively prevents acute and chronic rejection in rat renal allografts. Transplant Proc 2005; 37(1): 134-6.
[http://dx.doi.org/10.1016/j.transproceed.2004.12.054] [PMID: 15808572]
[58]
Krishna G, Liu K, Shigemitsu H, Gao M, Raffin TA, Rosen GD. PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis. Am J Pathol 2001; 158(3): 997-1004.
[http://dx.doi.org/10.1016/S0002-9440(10)64046-1] [PMID: 11238047]
[59]
Chen BJ, Chen Y, Cui X, Fidler JM, Chao NJ. Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model. Transplantation 2002; 73(1): 115-21.
[http://dx.doi.org/10.1097/00007890-200201150-00022] [PMID: 11792990]
[60]
Leonard CT, Soccal PM, Berry GJ, et al. PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model. J Heart Lung Transplant 2002; 21(12): 1314-8.
[61]
Zhou R, Zhang F, He PL, et al. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. Int Immunopharmacol 2005; 5(13-14): 1895-903.
[http://dx.doi.org/10.1016/j.intimp.2005.06.009] [PMID: 16275624]
[62]
Zhou R, Tang W, Ren YX, et al. Preventive effects of (5R)-5-hydroxytriptolide on concanavalin A-induced hepatitis. Eur J Pharmacol 2006; 537(1-3): 181-9.
[http://dx.doi.org/10.1016/j.ejphar.2006.03.013] [PMID: 16603150]
[63]
Zhou R, Tang W, He PL, Yang YF, Li YC, Zuo JP. (5R)-5-hydroxytriptolide inhibits the immune response of human peripheral blood mononuclear cells. Int Immunopharmacol 2009; 9(1): 63-9.
[http://dx.doi.org/10.1016/j.intimp.2008.09.014] [PMID: 18952005]
[64]
Liu J, Chen X, Zhang Y, et al. Derivatization of (5R)-hydroxytriptolide from benzylamine to enhance mass spectrometric detection: Application to a Phase I pharmacokinetic study in humans. Anal Chim Acta 2011; 689(1): 69-76.
[http://dx.doi.org/10.1016/j.aca.2011.01.016] [PMID: 21338759]
[65]
Carter BZ, Mak DH, Shi Y, et al. MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML. Leukemia 2012; 26(3): 443-50.
[http://dx.doi.org/10.1038/leu.2011.246] [PMID: 21904380]
[66]
Fidler JM, An J, Carter BZ, Andreeff M. Preclinical antileukemic activity, toxicology, toxicokinetics and formulation development of triptolide derivative MRx102. Cancer Chemother Pharmacol 2014; 73(5): 961-74.
[http://dx.doi.org/10.1007/s00280-014-2428-6] [PMID: 24619497]