Triptolide: structural modifications, structure-activity relationships, bioactivities, clinical development and mechanisms.

Triptolide, a principal bioactive ingredient of Tripterygium wilfordii Hook F, has attracted extensive exploration due to its unique structure of a diterpenoid triepoxide and multiple biological activities. This review will focus on the structural modifications, structure-activity relationships, pharmacology, and clinical development of triptolide in the last forty years.

[1]  M. Andreeff,et al.  MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML , 2012, Leukemia.

[2]  Li He,et al.  Triptolide (TPL) Inhibits Global Transcription by Inducing Proteasome-Dependent Degradation of RNA Polymerase II (Pol II) , 2011, PloS one.

[3]  Jim Hu,et al.  Complexity of dendritic cell subsets and their function in the host immune system , 2011, Immunology.

[4]  T. Corson,et al.  Triptolide Directly Inhibits dCTP Pyrophosphatase , 2011, Chembiochem : a European journal of chemical biology.

[5]  Z. Miao,et al.  Total synthesis of novel D-ring-modified triptolide analogues: structure-cytotoxic activity relationship studies on the D-ring of triptolide. , 2011, Organic & biomolecular chemistry.

[6]  M. Shu,et al.  Triptolide-induced cell cycle arrest and apoptosis in human renal cell carcinoma cells. , 2011, Oncology reports.

[7]  Xiaoyan Chen,et al.  Derivatization of (5R)-hydroxytriptolide from benzylamine to enhance mass spectrometric detection: application to a Phase I pharmacokinetic study in humans. , 2011, Analytica chimica acta.

[8]  Qiuyan Liu.  Triptolide and its expanding multiple pharmacological functions. , 2011, International immunopharmacology.

[9]  Jun O. Liu,et al.  XPB, a subunit of TFIIH, is a target of the natural product triptolide. , 2011, Nature chemical biology.

[10]  T. Nishida,et al.  Inhibition of poly(I:C)–induced matrix metalloproteinase expression in human corneal fibroblasts by triptolide , 2011, Molecular vision.

[11]  Hai-Feng Zhang,et al.  Triptolide augments the effects of 5-lipoxygenase RNA interference in suppressing pancreatic tumor growth in a xenograft mouse model , 2011, Cancer Chemotherapy and Pharmacology.

[12]  Y. Tsukamoto,et al.  Novel target genes responsive to the anti-growth activity of triptolide in endometrial and ovarian cancer cells. , 2010, Cancer letters.

[13]  Yan Chen,et al.  Role of triptolide in cell proliferation, cell cycle arrest, apoptosis and histone methylation in multiple myeloma U266 cells. , 2010, European journal of pharmacology.

[14]  Z. Miao,et al.  Synthesis and biological evaluation of novel triptolide analogues for anticancer activity. , 2010, Bioorganic & medicinal chemistry letters.

[15]  Min Jung Kim,et al.  Triptolide inactivates Akt and induces caspase-dependent death in cervical cancer cells via the mitochondrial pathway. , 2010, International journal of oncology.

[16]  Yi Chen,et al.  Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide , 2010, Molecular Cancer.

[17]  M. Antonoff,et al.  Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinoma. , 2010, The Journal of surgical research.

[18]  Jie-shou Li,et al.  Triptolide ameliorates IL-10-deficient mice colitis by mechanisms involving suppression of IL-6/STAT3 signaling pathway and down-regulation of IL-17. , 2010, Molecular immunology.

[19]  M. Antonoff,et al.  Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways. , 2010, Gastroenterology.

[20]  A. Wagner,et al.  Diastereoselective formal total synthesis of (+/-)-triptolide via a novel cationic cyclization of 2-alkenyl-1,3-dithiolane. , 2010, Chemical communications.

[21]  Yuanchao Li,et al.  Efficient synthesis of the key intermediate triptophenolide methyl ether for the synthesis of (-)-triptolide , 2010 .

[22]  F. Hyder,et al.  Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[23]  Jingxuan Pan.  RNA polymerase - an important molecular target of triptolide in cancer cells. , 2010, Cancer letters.

[24]  Miaojia Zhang,et al.  Report of 12 cases of ankylosing spondylitis patients treated with Tripterygium wilfordii , 2010, Clinical Rheumatology.

[25]  C. Zeng,et al.  Triptolide reduces proteinuria in experimental membranous nephropathy and protects against C5b-9-induced podocyte injury in vitro. , 2010, Kidney international.

[26]  Cheng He,et al.  Triptolide promotes spinal cord repair by inhibiting astrogliosis and inflammation , 2010, Glia.

[27]  Yan Chen,et al.  Effects of triptolide on RIZ1 expression, proliferation, and apoptosis in multiple myeloma U266 cells , 2010, Acta Pharmacologica Sinica.

[28]  Yanli Jin,et al.  Triptolide inhibits Jak2 transcription and induces apoptosis in human myeloproliferative disorder cells bearing Jak2V617F through caspase-3-mediated cleavage of Mcl-1. , 2010, Cancer letters.

[29]  Yanli Jin,et al.  Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl. , 2010, Bioorganic & medicinal chemistry.

[30]  Yan Chen,et al.  Triptolide alters histone H3K9 and H3K27 methylation state and induces G0/G1 arrest and caspase-dependent apoptosis in multiple myeloma in vitro. , 2010, Toxicology.

[31]  M. Shu,et al.  Anti-angiogenic activity of triptolide in anaplastic thyroid carcinoma is mediated by targeting vascular endothelial and tumor cells. , 2010, Vascular pharmacology.

[32]  C. Mei,et al.  Meta-analysis of Tripterygium wilfordii Hook F in the immunosuppressive treatment of IgA nephropathy. , 2010, Internal medicine.

[33]  I. Raskin,et al.  Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (EAE) by induction of HSP70 and stabilization of NF-κB/IκBα transcriptional complex , 2009, Journal of Neuroimmunology.

[34]  Tao Wang,et al.  Effects of triptolide from Tripterygium wilfordii on ERalpha and p53 expression in two human breast cancer cell lines. , 2009, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[35]  P. Marignani,et al.  Triptolide: An inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) in cancer cells , 2009, Cancer biology & therapy.

[36]  J. Annereau,et al.  Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA , 2009, Molecular Cancer Therapeutics.

[37]  Steven J. Skube,et al.  Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. , 2009, Surgery.

[38]  Z. Miao,et al.  Design and synthesis of novel C14-hydroxyl substituted triptolide derivatives as potential selective antitumor agents. , 2009, Journal of medicinal chemistry.

[39]  A. Lu,et al.  Effects of triptolide from Radix Tripterygium wilfordii (Leigongteng) on cartilage cytokines and transcription factor NF-κB: a study on induced arthritis in rats , 2009, Chinese medicine.

[40]  S. Gordon,et al.  Alternative activation of macrophages: immune function and cellular biology. , 2009, Immunobiology.

[41]  H. Sytwu,et al.  Triptolide exerts anti-tumor effect on oral cancer and KB cells in vitro and in vivo. , 2009, Oral oncology.

[42]  J. Verweij,et al.  Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. , 2009, European Journal of Cancer.

[43]  M. Shu,et al.  A Small-Molecule Triptolide Suppresses Angiogenesis and Invasion of Human Anaplastic Thyroid Carcinoma Cells via Down-Regulation of the Nuclear Factor-κB Pathway , 2009, Molecular Pharmacology.

[44]  Yanli Jin,et al.  Triptolide Inhibits Bcr-Abl Transcription and Induces Apoptosis in STI571-resistant Chronic Myelogenous Leukemia Cells Harboring T315I Mutation , 2009, Clinical Cancer Research.

[45]  W. Ge,et al.  Antiangiogenic activity of Tripterygium wilfordii and its terpenoids. , 2009, Journal of ethnopharmacology.

[46]  Tao Wang,et al.  Male Reproductive Toxicity and Toxicokinetics of Triptolide in Rats , 2008, Arzneimittel-Forschung (Drug Research).

[47]  M. Ji,et al.  Prolongation of rat intestinal allograft survival by administration of triptolide-modified donor bone marrow-derived dendritic cells. , 2008, Transplantation proceedings.

[48]  Jie-shou Li,et al.  The suppressive effect of triptolide on chronic colitis and TNF-alpha/TNFR2 signal pathway in interleukin-10 deficient mice. , 2008, Clinical immunology.

[49]  Changyou Wu,et al.  Triptolide Inhibits the Differentiation of Th17 cells and Suppresses Collagen‐induced Arthritis , 2008, Scandinavian journal of immunology.

[50]  P. Igarashi,et al.  Triptolide reduces cystogenesis in a model of ADPKD. , 2008, Journal of the American Society of Nephrology : JASN.

[51]  Y. Mei,et al.  Triptolide modulates T‐cell inflammatory responses and ameliorates experimental autoimmune encephalomyelitis , 2008, Journal of neuroscience research.

[52]  S. Leuenroth,et al.  Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure. , 2008, Cancer Research.

[53]  P. Lipsky,et al.  Effective therapy for nephritis in (NZB x NZW)F1 mice with triptolide and tripdiolide, the principal active components of the Chinese herbal remedy Tripterygium wilfordii Hook F. , 2008, Arthritis and rheumatism.

[54]  D. Chang,et al.  Differential effects of triptolide and tetrandrine on activation of COX-2, NF-κB, and AP-1 and virus production in dengue virus-infected human lung cells , 2008, European Journal of Pharmacology.

[55]  T. Matsuzaki,et al.  Fluorination of triptolide and its analogues and their cytotoxicity. , 2008, Bioorganic & medicinal chemistry letters.

[56]  A. Willis,et al.  Formal total synthesis of triptolide. , 2008, Chemical communications.

[57]  L. Vassilev,et al.  Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5. , 2006, Blood.

[58]  Min Yang,et al.  Triptolide overcomes dexamethasone resistance and enhanced PS-341-induced apoptosis via PI3k/Akt/NF-kappaB pathways in human multiple myeloma cells. , 2008, International journal of molecular medicine.

[59]  L. Feng,et al.  Inhibitory effect of triptolide on interleukin-18 and its receptor in rheumatoid arthritis synovial fibroblasts , 2008, Inflammation Research.

[60]  M. Skinner,et al.  Role of Triptolide as an Adjunct Chemotherapy for Ovarian Cancer , 2007, Chemotherapy.

[61]  W. Grizzle,et al.  Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. , 2007, Cancer research.

[62]  Craig M. Crews,et al.  Molecular Understanding and Modern Application of Traditional Medicines: Triumphs and Trials , 2007, Cell.

[63]  P. Okunieff,et al.  Enhanced Antitumor Effect of Combined Triptolide and Ionizing Radiation , 2007, Clinical Cancer Research.

[64]  Xiao-yan Tang,et al.  Synergistic effect of triptolide combined with 5-fluorouracil on colon carcinoma , 2007, Postgraduate Medical Journal.

[65]  Jie-shou Li,et al.  Efficacy of T2 in Active Crohn’s Disease: A Prospective Study Report , 2007, Digestive Diseases and Sciences.

[66]  Taoyong Chen,et al.  Triptolide impairs dendritic cell migration by inhibiting CCR7 and COX-2 expression through PI3-K/Akt and NF-kappaB pathways. , 2007, Molecular immunology.

[67]  S. Somlo,et al.  Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease , 2007, Proceedings of the National Academy of Sciences.

[68]  P. Lipsky,et al.  Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). , 2007, Phytochemistry.

[69]  H. Cheung,et al.  Triptolide induces Bcl-2 cleavage and mitochondria dependent apoptosis in p53-deficient HL-60 cells. , 2006, Cancer letters.

[70]  Z. Estrov,et al.  Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells. , 2006, Blood.

[71]  H. Fujiwara,et al.  (5R)-5-Hydroxytriptolide Attenuated Collagen-Induced Arthritis in DBA/1 Mice via Suppressing Interferon-γ Production and Its Related Signaling , 2006, Journal of Pharmacology and Experimental Therapeutics.

[72]  L. Li,et al.  Clinical trial of Tripterygium Wilfordii Hook F. in human kidney transplantation in China. , 2006, Transplantation proceedings.

[73]  Wei Tang,et al.  (5R)-5-Hydroxytriptolide (LLDT-8), a novel triptolide derivative, prevents experimental autoimmune encephalomyelitis via inhibiting T cell activation , 2006, Journal of Neuroimmunology.

[74]  Wei Tang,et al.  Preventive effects of (5R)-5-hydroxytriptolide on concanavalin A-induced hepatitis. , 2006, European journal of pharmacology.

[75]  S. Westerheide,et al.  Triptolide, an Inhibitor of the Human Heat Shock Response That Enhances Stress-induced Cell Death* , 2006, Journal of Biological Chemistry.

[76]  Jian-Ping Zuo,et al.  Suppression of (5R)-5-hydroxytriptolide (LLDT-8) on Allograft Rejection in Full MHC-Mismatched Mouse Cardiac Transplantation , 2006, Transplantation.

[77]  Yuanyuan Wu,et al.  Triptolide attenuates oxidative stress, NF-kappaB activation and multiple cytokine gene expression in murine peritoneal macrophage. , 2006, International journal of molecular medicine.

[78]  Wei Tang,et al.  (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. , 2005, International immunopharmacology.

[79]  Jian-Ping Zuo,et al.  Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells. , 2005, International immunopharmacology.

[80]  S. Leuenroth,et al.  Studies on calcium dependence reveal multiple modes of action for triptolide. , 2005, Chemistry & biology.

[81]  Xin Chen,et al.  Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking. , 2005, Blood.

[82]  X. Mao,et al.  Triptolide affects the differentiation, maturation and function of human dendritic cells. , 2005, International immunopharmacology.

[83]  I. Raskin,et al.  Determination of triptolide in root extracts of Tripterygium wilfordii by solid-phase extraction and reverse-phase high-performance liquid chromatography. , 2005, Journal of chromatography. A.

[84]  D. Zaller,et al.  In vitro versus in vivo effects of triptolide: the role of transcriptional inhibition , 2005 .

[85]  M. Zafarullah,et al.  Triptolide suppresses proinflammatory cytokine-induced matrix metalloproteinase and aggrecanase-1 gene expression in chondrocytes. , 2005, Biochemical and biophysical research communications.

[86]  Jian-Ping Zuo,et al.  Triptolide suppresses CD80 and CD86 expressions and IL-12 production in THP-1 cells , 2005, Acta Pharmacologica Sinica.

[87]  H. Young,et al.  Triptolide Attenuates Endotoxin- and Staphylococcal Exotoxin-Induced T-Cell Proliferation and Production of Cytokines and Chemokines , 2005, Immunopharmacology and immunotoxicology.

[88]  K. Takazawa,et al.  Synergistic effect of triptolide and tacrolimus on rat cardiac allotransplantation. , 2004, Japanese heart journal.

[89]  M. Blagosklonny,et al.  Flavopiridol Induces p53 via Initial Inhibition of Mdm2 and p21 and, Independently of p53, Sensitizes Apoptosis-Reluctant Cells to Tumor Necrosis Factor , 2004, Cancer Research.

[90]  Ling-Jun Ho,et al.  Chinese herbs as immunomodulators and potential disease-modifying antirheumatic drugs in autoimmune disorders. , 2004, Current drug metabolism.

[91]  Yadi Wu,et al.  The suppressive effect of triptolide on experimental autoimmune uveoretinitis by down-regulating Th1-type response. , 2003, International immunopharmacology.

[92]  J. A. Ross,et al.  PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy. , 2003, Molecular cancer therapeutics.

[93]  John Calvin Reed,et al.  PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2 , 2003, Oncogene.

[94]  Lurong Zhang,et al.  Triptolide inhibits the growth and metastasis of solid tumors. , 2003, Molecular cancer therapeutics.

[95]  P. Kao,et al.  Immunosuppressive and Anti-Inflammatory Mechanisms of Triptolide, the Principal Active Diterpenoid from the Chinese Medicinal Herb Tripterygium wilfordii Hook. f. , 2003, Drugs in R&D.

[96]  G. Rosen,et al.  Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-κB activation , 2002, Experimental & Molecular Medicine.

[97]  R. Sellers,et al.  Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[98]  P. Lipsky,et al.  Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. , 2002, Arthritis and rheumatism.

[99]  B. Wong,et al.  Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-κB activation in gastric cancer cells , 2001, Oncogene.

[100]  T. Sato,et al.  Triptolide, a novel diterpenoid triepoxide from Tripterygium wilfordii Hook. f., suppresses the production and gene expression of pro-matrix metalloproteinases 1 and 3 and augments those of tissue inhibitors of metalloproteinases 1 and 2 in human synovial fibroblasts. , 2001, Arthritis and rheumatism.

[101]  J. A. Ross,et al.  Triptolide and Chemotherapy Cooperate in Tumor Cell Apoptosis , 2001, The Journal of Biological Chemistry.

[102]  Benny J Chen,et al.  Triptolide, A Novel Immunosuppressive and Anti-Inflammatory Agent Purified from a Chinese Herb Tripterygium Wilfordii Hook F , 2001, Leukemia & lymphoma.

[103]  H. Davis,et al.  Role of MARCKS in regulating endothelial cell proliferation. , 2000, American journal of physiology. Cell physiology.

[104]  R. Swerdloff,et al.  Long-term effects of triptolide on spermatogenesis, epididymal sperm function, and fertility in male rats. , 2000, Journal of andrology.

[105]  J. Wang,et al.  Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. I. Prolongation of rat cardiac and renal allograft survival by the PG27 extract and immunosuppressive synergy in combination therapy with cyclosporine. , 2000 .

[106]  R. Swerdloff,et al.  Posttesticular antifertility action of triptolide in the male rat: evidence for severe impairment of cauda epididymal sperm ultrastructure. , 2000, Journal of andrology.

[107]  M. Xu,et al.  Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinonide. , 2000, The Journal of organic chemistry.

[108]  P. Lipsky,et al.  The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. , 2000, Rheumatic diseases clinics of North America.

[109]  G. Rosen,et al.  PG490 (Triptolide) Cooperates with Tumor Necrosis Factor-α to Induce Apoptosis in Tumor Cells* , 1999, The Journal of Biological Chemistry.

[110]  P. Kao,et al.  Immunosuppressant PG490 (Triptolide) Inhibits T-cell Interleukin-2 Expression at the Level of Purine-box/Nuclear Factor of Activated T-cells and NF-κB Transcriptional Activation* , 1999, The Journal of Biological Chemistry.

[111]  V. Reutrakul,et al.  Antitumor activity of triptolide against cholangiocarcinoma growth in vitro and in hamsters. , 1998, Cancer letters.

[112]  Y. Yang,et al.  Triptolide induces apoptotic death of T lymphocyte. , 1998, Immunopharmacology.

[113]  R. Swerdloff,et al.  Triptolide: a potential male contraceptive. , 1998, Journal of andrology.

[114]  P. Lipsky,et al.  A potential new treatment for rheumatoid arthritis: thunder god vine. , 1997, Seminars in arthritis and rheumatism.

[115]  J. Pezzuto,et al.  Evaluation of the mutagenic, cytotoxic, and antitumor potential of triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii. , 1997, Cancer letters.

[116]  Q S Zhen,et al.  Recent progress in research on Tripterygium: a male antifertility plant. , 1995, Contraception.

[117]  H. Gao,et al.  Triptolide suppresses T-lymphocyte proliferation by inhibiting interleukin-2 receptor expression, but spares interleukin-2 production and mRNA expression. , 1994, International journal of immunopharmacology.

[118]  S. Matlin,et al.  Male antifertility compounds from Tripterygium wilfordii Hook f. , 1993, Contraception.

[119]  W. R. Zhang,et al.  Immunosuppression of triptolide and its effect on skin allograft survival. , 1992, International journal of immunopharmacology.

[120]  L. Davis,et al.  Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness. , 1991, Arthritis and rheumatism.

[121]  G. A. Berchtold,et al.  Total synthesis of racemic triptolide and triptonide , 1982 .

[122]  E. G. Taylor,et al.  Total synthesis of l-triptonide and l-triptolide , 1980 .

[123]  G. A. Berchtold,et al.  Total synthesis of triptolide and triptonide , 1980 .

[124]  G. A. Berchtold,et al.  Studies on the total synthesis of triptolide. I. , 1977, The Journal of organic chemistry.

[125]  S. M. Kupchan,et al.  Selective Alkylation: A Biomimetic Reaction of the Antileukemic Triptolides? , 1974, Science.

[126]  C. Gilmore,et al.  Triptolide and tripdiolide, novel antileukemic diterpenoid triepoxides from Tripterygium wilfordii. , 1972, Journal of the American Chemical Society.