Mechanism of Triptolide-induced Apoptosis: Effect on Caspase Activation and Bid Cleavage and Essentiality of the Hydroxyl Group of Triptolide

Overview

Journal J Mol Med (Berl)

Specialty General Medicine

Date 2005 Dec 31

PMID 16385419

Citations 15

Authors

Xianxi Wang

Ranyia Matta

Gang Shen

Leif D Nelin

Dehua Pei

Yusen Liu

Affiliations

Soon will be listed here.

Abstract

Triptolide is a compound extracted from the Chinese herb Tripterygium wilfordii Hook. f. Triptolide has potent anticancer activity. However, the mechanisms by which triptolide exerts its anticancer activities remain unclear. To explore the molecular mechanisms involved in the anticancer activity of triptolide, we have examined the effect of triptolide on the growth of pancreatic carcinoma PANC-1 and cervical adenocarcinoma HeLa cells. We found that treatment of both HeLa and PANC-1 cells with triptolide potently suppressed cell growth and induced apoptosis, indicated by nuclear fragmentation and blebbing. In both HeLa and PANC-1 cells, apoptosis induced by triptolide was associated with activation of both caspase-3 and caspase-8, and cleavage of poly(ADP-ribose) polymerase and Bid. Moreover, in HeLa cells, caspase-9 is also significantly activated in response to triptolide. Overexpression of Bcl-2 in HeLa cells substantially attenuated triptolide-induced apoptosis. Interestingly, substitution of the 14-OH of triptolide with an acetyl group abrogated both its anticancer and its antiinflammatory activities. Our studies suggest that triptolide may exert its anticancer effects by initiating apoptosis through both death-receptor- and mitochondria-mediated pathways. Our results indicate that both the apoptosis-promoting and the antiinflammatory activities of triptolide depend on the 14-OH group.

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References

Tao X, Younger J, Fan F, Wang B, Lipsky P . 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. DOI: 10.1002/art.10411. View

Mei Z, Li X, Wu Q, Hu S, Yang X . The research on the anti-inflammatory activity and hepatotoxicity of triptolide-loaded solid lipid nanoparticle. Pharmacol Res. 2005; 51(4):345-51. DOI: 10.1016/j.phrs.2004.10.007. View

Chen W, Martindale J, Holbrook N, Liu Y . Tumor promoter arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc. Mol Cell Biol. 1998; 18(9):5178-88. PMC: 109103. DOI: 10.1128/MCB.18.9.5178. View

Kiviharju T, Lecane P, Sellers R, Peehl D . Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells. Clin Cancer Res. 2002; 8(8):2666-74. View

Redston M, Caldas C, Seymour A, Hruban R, Da Costa L, Yeo C . p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994; 54(11):3025-33. View

Fidler J, Li K, Chung C, Wei K, Ross J, Gao M . PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy. Mol Cancer Ther. 2003; 2(9):855-62. View

Tao X, Cai J, Lipsky P . The identity of immunosuppressive components of the ethyl acetate extract and chloroform methanol extract (T2) of Tripterygium wilfordii Hook. F. J Pharmacol Exp Ther. 1995; 272(3):1305-12. View

Tao X, Lipsky P . The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. Rheum Dis Clin North Am. 2000; 26(1):29-50, viii. DOI: 10.1016/s0889-857x(05)70118-6. View

Yang S, Chen J, Guo Z, Xu X, Wang L, Pei X . Triptolide inhibits the growth and metastasis of solid tumors. Mol Cancer Ther. 2003; 2(1):65-72. View

10.

Reed J . Bcl-2 family proteins: regulators of chemoresistance in cancer. Toxicol Lett. 1995; 82-83:155-8. DOI: 10.1016/0378-4274(95)03551-6. View

11.

Zhao Q, Shepherd E, Manson M, Nelin L, Sorokin A, Liu Y . The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J Biol Chem. 2004; 280(9):8101-8. DOI: 10.1074/jbc.M411760200. View

12.

Lowe S, Schmitt E, Smith S, Osborne B, Jacks T . p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993; 362(6423):847-9. DOI: 10.1038/362847a0. View

13.

Han J, Thompson P, Beutler B . Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med. 1990; 172(1):391-4. PMC: 2188134. DOI: 10.1084/jem.172.1.391. View

14.

May E, Jenkins J, May P . Endogenous HeLa p53 proteins are easily detected in HeLa cells transfected with mouse deletion mutant p53 gene. Oncogene. 1991; 6(8):1363-5. View

15.

Li J, Gorospe M, Hutter D, Barnes J, Keyse S, Liu Y . Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. Mol Cell Biol. 2001; 21(23):8213-24. PMC: 99986. DOI: 10.1128/MCB.21.23.8213-8224.2001. View

16.

Wu J, Bennett A . Essential role for mitogen-activated protein (MAP) kinase phosphatase-1 in stress-responsive MAP kinase and cell survival signaling. J Biol Chem. 2005; 280(16):16461-6. DOI: 10.1074/jbc.M501762200. View

17.

Chen C, Edelstein L, Gelinas C . The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol. 2000; 20(8):2687-95. PMC: 85484. DOI: 10.1128/MCB.20.8.2687-2695.2000. View

18.

Chen M, Wang J . Initiator caspases in apoptosis signaling pathways. Apoptosis. 2002; 7(4):313-9. DOI: 10.1023/a:1016167228059. View

19.

Chen P, Li J, Barnes J, Kokkonen G, Lee J, Liu Y . Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. J Immunol. 2002; 169(11):6408-16. DOI: 10.4049/jimmunol.169.11.6408. View

20.

Green D . Apoptotic pathways: ten minutes to dead. Cell. 2005; 121(5):671-4. DOI: 10.1016/j.cell.2005.05.019. View