Parthenolide induces proliferation inhibition and apoptosis of pancreatic cancer cells in vitro

Jun-Wei Liu1, Minxia Cai2, Ying Xin1, Qingsong Wu1, Jun Ma1, Po Sheng Yang1, Haiyang Xie2, Dongsheng Huang1
1Department of General Surgery, Sir Run Run Shaw Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, PR China
2Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Department of Hepato-Biliary-Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China

Tóm tắt

Abstract Background To explore the anti-tumor effects of parthenolide in human pancreatic cancer. Methods BxPC-3 cell, a human pancreatic cancer, was treated with parthenolide at different concentrations. The MTT assay was used to analyze cell viability. Flow cytometry and DNA fragmentation analysis were applied to evaluate apoptosis after parthenolide treatment. The wound closure and cell invasion assay were also employed in the study. Western blotting was used to demonstrate Bad, Bcl-2, Bax, caspase-9 and pro-caspase-3 expression. Results The MTT assay indicated that the pancreatic cancer growth could be dose-dependently inhibited by parthenoolide. This phenomenon was confirmed by flow cytometry and DNA fragmentation analysis. The wound closure assay and cell invasion assay showed that BxPC-3 cell was significantly suppressed by parthenolide at 7.5 μM and 15 μM. Western Blotting demonstrated the Bcl-2 and pro-caspase-3 were down-regulated while the Bax and caspase-9 were up-regulated. No alteration in Bad expression was found after treatment. Conclusions The parthenolide can inhibit the cell growth, migration, and induce the apoptosis in human pancreatic cancer. These findings may provide a novel approach for pancreatic cancer treatment.

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Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ: Cancer statistics, 2004. CA-Cancer J Clin. 2004, 54: 8-29. 10.3322/canjclin.54.1.8.

Safioleas MC, Moulakakis KG: Pancreatic cancer today. Hepatogastroenterology. 2004, 51: 862-868.

Pozarowski P, Halicka DH, Parzykiewicz Z: NF-kappaB inhibitor sesquiterpene parthenolide induces concurrently a typical apoptosis and cell necrosis: difficulties in identification of dead cells in such cultures. Cytometry A. 2003, 54: 118-124. 10.1002/cyto.a.10057.

Zhang S, Ong CN, Shen HM: Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 2004, 208: 143-153. 10.1016/j.canlet.2003.11.028.

Park JH, Liu L, Kim IH, Kim JH, You KR, Kim DG: Identification of the genes involved in enhanced fenretinide-induced apoptosis by parthenolide in human hepatoma cells. Cancer Res. 2005, 65: 2804-2814. 10.1158/0008-5472.CAN-04-2221.

Kim JH, Liu L, Lee SO, Kim YT, You KR, Kim DG: Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis. Cancer Res. 2005, 65: 6312-6320. 10.1158/0008-5472.CAN-04-4193.

Zhang S, Lin ZN, Yang CF, Shi X, Ong CN, Shen HM: Suppressed NF-{kappa}B and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF-{alpha}-induced apoptosis in human cancer cells. Carcinogenesis. 2004, 25: 2191-2199. 10.1093/carcin/bgh234.

Nakshatri H, Rice SE, Bhat-Nakshatri P: Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene. 2004, 23: 7330-7344. 10.1038/sj.onc.1207995.

Won YK, Ong CN, Shi X, Shen HM: Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms. Carcinogenesis. 2004, 25: 1449-1458. 10.1093/carcin/bgh151.

Yip-Schneider MT, Nakshatri H, Sweeney CJ, Marshall MS, Wiebke EA, Schmidt CM: Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells. Mol Cancer Ther. 2005, 4: 587-594. 10.1158/1535-7163.MCT-04-0215.

Ross JJ, Arnason JT, Birnboim HC: Low concentrations of the feverfew component parthenolide inhibit in vitro growth of tumor lines in a cytostatic fashion. Planta Med. 1999, 65: 126-129. 10.1055/s-1999-13972.

Wen J, You KR, Lee SY, Song CH, Kim DG: Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem. 2002, 277: 38954-38964. 10.1074/jbc.M203842200.

Hanahan D, Weinberg RA: The hallmarks of cancer. Cell. 2000, 100: 57-70. 10.1016/S0092-8674(00)81683-9.

Fulda S, Debatin KM: Death receptor signaling in cancer therapy. Curr Med Chem Anti-Canc Agents. 2003, 3: 253-262. 10.2174/1568011033482404.

Wang W, Abbruzzese JL, Evans DB, Chiao PJ: Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene. 1999, 18: 4554-4563. 10.1038/sj.onc.1202833.

Greten FR, Weber CK, Greten TF, Schneider G, Wagner M, Adler G, Schmid RM: Stat3 and NF-λB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology. 2002, 123: 2052-2063. 10.1053/gast.2002.37075.

Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Crews CM: The anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IkB kinase. Chem Biol. 2001, 8: 759-766. 10.1016/S1074-5521(01)00049-7.

Yip-Schneider MT, Wu H, Njoku V, Ralstin M, Holcomb B, Crooks PA, Neelakantan S, Sweeney CJ, Schmidt CM: Effect of celecoxib and the novel anti-cancer agent, dimethylamino-parthenolide, in a developmental model of pancreatic cancer. Pancreas. 2008, 37: e45-e53. 10.1097/MPA.0b013e318172b4dd.

Yip-Schneider MT, Wu H, Ralstin M, Yiannoutsos C, Crooks PA, Neelakantan S, Noble S, Nakshatri H, Sweeney CJ, Schmidt CM: Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo. Mol Cancer Ther. 2007, 6: 1736-1744. 10.1158/1535-7163.MCT-06-0794.

Wang W, Adachi M, Zhang R, Zhou J, Zhu D: A novel combination therapy with arsenic trioxide and parthenolide against pancreatic cancer cells. Pancreas. 2009, 38: e114-e123. 10.1097/MPA.0b013e3181a0b6f2.

Adams JM, Cory S: The Bcl-2 protein family: Arbiters of cell survival. Science. 1998, 281: 1322-1326. 10.1126/science.281.5381.1322.

Gross A, McDonnell JM, Korsmeyer SJ: Bcl-2 family members and the mitochondria in apoptosis. Gene Dev. 1999, 13: 1899-1911. 10.1101/gad.13.15.1899.

Dong M, Zhou JP, Zhang H, Guo KJ, Tian YL, Dong YT: Clinicopathological significance of Bcl-2 and Bax protein expression in human pancreatic cancer. World J G. 2005, 11: 2744-2747.

Wang CY, Guttridge DC, Mayo MW, Baldwin AS: NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol. 1999, 19: 5923-5929.

Kurland JF, Kodym R, Story MD, Spurgers KB, McDonnell TJ, Meyn RE: NF-kB1 (p50) homodimers contribute to transcription of the bcl-2 oncogene. J Biol Chem. 2001, 276: 45380-45386. 10.1074/jbc.M108294200.

Viatour P, Bentires-Alj M, Chariot A, Deregowski V, de Leval L, Merville MP, Bours V: NF-kappa B2/p100 induces Bcl-2 expression. Leukemia. 2003, 17: 1349-1356. 10.1038/sj.leu.2402982.

Catz SD, Johnson JL: Transcriptional regulation of Bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene. 2001, 20: 7342-7345. 10.1038/sj.onc.1204926.

Fahy BN, Schlieman MG, Mortenson MM, Virudachalam S, Bold RJ: Targeting BCL-2 overexpression in various human malignancies through Nf-kappaB inhibition by the proteasome inhibitor bortezomib. Cancer Chemother Pharmaco1. 2005, 56: 46-54. 10.1007/s00280-004-0944-5.

Salvesen GS, Dixit VM: Caspases: mtracellular signaling by proteolysis. Cell. 1997, 91: 443-446. 10.1016/S0092-8674(00)80430-4.

Du C, Fang M, Li Y, Wang X, Smac A: Mitochondrial protein that promotes cytochrome-c dependent caspase activation by eliminating IAP inhibition. Cell. 2000, 102: 43-53. 10.1016/S0092-8674(00)00008-8.

Zou H, Li Y, Liu X, Wang X: An APAF-1.cytochrome-c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999, 274: 11549-11556. 10.1074/jbc.274.17.11549.