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Synergism of Cytotoxicity Effects of Triptolide and Artesunate Combination Treatment in Pancreatic Cancer Cell Lines

  • Liu, Yao (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University) ;
  • Cui, Yun-Fu (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University)
  • Published : 2013.09.30

Abstract

Background: Triptolide, extracted from the herb Tripteryglum wilfordii Hook.f that has long been used as a natural medicine in China, has attracted much interest for its anti-cancer effects against some kinds of tumours in recent years. Artesunate, extracted from the Chinese herb Artemisia annua, has proven to be effective and safe as an anti-malarial drug that possesses anticancer potential. The present study attempted to clarify if triptolide enhances artesunate-induced cytotoxicity in pancreatic cancer cell lines in vitro and in vivo. Methods: In vitro, to test synergic actions, cell viability and apoptosis were analyzed after treatment of pancreatic cancer cell lines with the two agents singly or in combination. The molecular mechanisms of apoptotic effects were also explored using qRT-PCR and Western blotting. In vivo, a tumor xenograft model was established in nude mice, for assessment of inhibitory effects of triptolide and artesunate. Results: We could show that the combination of triptolide and artesunate could inhibit pancreatic cancer cell line growth, and induce apoptosis, accompanied by expression of HSP 20 and HSP 27, indicating important roles in the synergic effects. Moreover, tumor growth was decreased with triptolide and artesunate synergy. Conclusion: Our result indicated that triptolide and artesunate in combination at low concentrations can exert synergistic anti-tumor effects in pancreatic cancer cells with potential clinical applications.

Keywords

Triptolide;artesunate;pancreatic cancer cell lines;cytotoxicity;synergism

References

  1. Du JH, Zhang HD, Ma ZJ, Ji KM (2010). Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother Pharmacol, 65, 895-902. https://doi.org/10.1007/s00280-009-1095-5
  2. Bachmeier B, Fichtner I, Killian PH, et al (2011). Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells. PLoS One, 6, e20550. https://doi.org/10.1371/journal.pone.0020550
  3. Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B (2011). Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells. Mol Cancer Ther, 10, 2224-33. https://doi.org/10.1158/1535-7163.MCT-11-0534
  4. Cappello F, Angileri F, de Macario EC, Macario AJ (2013). Chaperonopathies and chaperonotherapy. Hsp60 as therapeutic target in cancer: potential benefits and risks. Curr Pharm Des, 19, 452-7. https://doi.org/10.2174/138161213804143653
  5. Chen H, Shi L, Yang X, et al (2010). Artesunate inhibiting angiogenesis induced by human myeloma RPMI8226 cells. Int J Hematol, 92, 587-97. https://doi.org/10.1007/s12185-010-0697-3
  6. Chueh FS, Chen YL, Hsu SC, et al (2013). Triptolide induced DNA damage in A375.S2 human malignant melanoma cells is mediated via reduction of DNA repair genes. Oncol Rep, 29, 613-8. https://doi.org/10.3892/or.2012.2170
  7. Edwards HV, Cameron RT, Baillie GS (2011). The emerging role of HSP20 as a multifunctional protective agent. Cell Signal, 23, 1447-54. https://doi.org/10.1016/j.cellsig.2011.05.009
  8. Guo K, Liu Y, Zhou H, et al (2008). Involvement of protein kinase C beta-extracellular signal-regulating kinase 1/2/ p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion. Cancer Sci, 99, 486-96. https://doi.org/10.1111/j.1349-7006.2007.00702.x
  9. He RR, Zhou HJ (2008). Progress in research on the anti-tumor effect of artesunate. Chin J Integr Med, 14, 312-6. https://doi.org/10.1007/s11655-008-0312-0
  10. Hjerpe E, Egyhazi S, Carlson J, et al (2013). HSP60 Predicts Survival in Advanced Serous Ovarian Cancer. Int J Gynecol Cancer, 23, 448-55. https://doi.org/10.1097/IGC.0b013e318284308b
  11. Huang M, Zhang H, Liu T, et al (2013). Triptolide Inhibits MDM2 and Induces Apoptosis in Acute Lymphoblastic Leukemia Cells through a p53-Independent Pathway. Mol Cancer Ther, 12, 184-94. https://doi.org/10.1158/1535-7163.MCT-12-0425
  12. Huang W, He T, Chai C, et al (2012). Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression. PLoS One, 7, e37693. https://doi.org/10.1371/journal.pone.0037693
  13. Li PC, Lam E, Roos WP, et al (2008). Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res, 68, 4347-51. https://doi.org/10.1158/0008-5472.CAN-07-2970
  14. Hung FM, Chen YL, Huang AC, et al (2013). Triptolide induces S phase arrest via the inhibition of cyclin E and CDC25A and triggers apoptosis via caspase- and mitochondrial-dependent signaling pathways in A375.S2 human melanoma cells. Oncol Rep, 29, 1053-60. https://doi.org/10.3892/or.2013.2230
  15. Jiang Z, Chai J, Chuang HH, et al (2012). Artesunate induces G0/G1 cell cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells. Anticancer Drugs, 23, 606-13. https://doi.org/10.1097/CAD.0b013e328350e8ac
  16. Li H, Hui L, Xu W, et al (2012). Triptolide modulates the sensitivity of K562/A02 cells to adriamycin by regulating miR-21 expression. Pharm Biol, 50, 1233-40. https://doi.org/10.3109/13880209.2012.665931
  17. Ma H, Yao Q, Zhang AM, et al (2011). The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model. Molecules, 16, 10556-69. https://doi.org/10.3390/molecules161210556
  18. Mao ZG, Zhou J, Wang H, et al (2012). Artesunate inhibits cell proliferation and decreases growth hormone synthesis and secretion in GH3 cells. Mol Biol Rep, 39, 6227-34. https://doi.org/10.1007/s11033-011-1442-6
  19. Matsushima-Nishiwaki R, Takai S, Adachi S, et al (2008). Phosphorylated heat shock protein 27 represses growth of hepatocellular carcinoma via inhibition of extracellular signal-regulated kinase. J Biol Chem, 283, 18852-60. https://doi.org/10.1074/jbc.M801301200
  20. Matsushima-Nishiwaki R, Adachi S, Yoshioka T, et al (2011). Suppression by heat shock protein 20 of hepatocellular carcinoma cell proliferation via inhibition of the mitogenactivated protein kinases and AKT pathways. J Cell Biochem, 112, 3430-9. https://doi.org/10.1002/jcb.23270
  21. Noda T, Kumada T, Takai S, et al (2007). Expression levels of heat shock protein 20 decrease in parallel with tumor progression in patients with hepatocellular carcinoma. Oncol Rep, 17, 1309-14.
  22. Xiaowen H, Yi S (2012). Triptolide sensitizes TRAIL-induced apoptosis in prostate cancer cells via p53-mediated DR5 up-regulation. Mol Biol Rep, 39, 8763-70. https://doi.org/10.1007/s11033-012-1737-2
  23. Tao Y, Zhang ML, Ma PC, et al (2012). Triptolide inhibits proliferation and induces apoptosis of human melanoma A375 cells. Asian Pac J Cancer Prev, 13, 1611-5. https://doi.org/10.7314/APJCP.2012.13.4.1611
  24. Thanaketpaisarn O, Waiwut P, Sakurai H, Saiki I (2011). Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-$\kappa{B}$ and PI3K/Akt signaling pathways. Int J Oncol, 39, 279-85.
  25. Wang W, Lin W, Hong B, et al (2012). Effect of triptolide on malignant peripheral nerve sheath tumours in vitro and in vivo. J Int Med Res, 40, 2284-94. https://doi.org/10.1177/030006051204000626
  26. Youns M, Efferth T, Reichling J, et al (2009). Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells. Biochem Pharmacol, 78, 273-83. https://doi.org/10.1016/j.bcp.2009.04.014
  27. Zhang H, Zhu W, Su X, et al (2012). Triptolide inhibits proliferation and invasion of malignant glioma cells. J Neurooncol, 109, 53-62. https://doi.org/10.1007/s11060-012-0885-5
  28. Zhou C, Pan W, Wang XP, Chen TS (2012). Artesunate induces apoptosis via a Bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. J Cell Physiol, 227, 3778-86. https://doi.org/10.1002/jcp.24086
  29. Zhao Y, Jiang W, Li B, et al (2011). Artesunate enhances radiosensitivity of human non-small cell lung cancer A549 cells via increasing NO production to induce cell cycle arrest at G2/M phase. Int Immunopharmacol, 11, 2039-46. https://doi.org/10.1016/j.intimp.2011.08.017

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