The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Antitumor Effects of Camptothecin Combined with Conventional Anticancer Drugs on the Cervical and Uterine Squamous Cell Carcinoma Cell Line SiHa

  • Ha, Sang-Won (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Kim, Yun-Jeong (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Kim, Won-Yong (Department of Microbiology, College of Medicine, Chung-Ang University) ;
  • Lee, Chung-Soo (Department of Pharmacology, College of Medicine, Chung-Ang University)
  • Published : 2009.04.30
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Abstract

Functional defects in mitochondria are involved in the induction of cell death in cancer cells. We assessed the toxic effect of camptothecin against the human cervical and uterine tumor cell line SiHa with respect to the mitochondria-mediated cell death process, and examined the combined effect of camptothecin and anticancer drugs. Camptothecin caused apoptosis in SiHa cells by inducing mitochondrial membrane permeability changes that lead to the loss of mitochondrial membrane potential, decreased Bcl-2 levels, cytochrome c release, caspase-3 activation, formation of reactive oxygen species and depletion of GSH. Combination of camptothecin with other anticancer drugs (carboplatin, paclitaxel, doxorubicin and mitomycin c) or signaling inhibitors (farnesyltransferase inhibitor and ERK inhibitor) did not enhance the camptothecin-induced cell death and caspase-3 activation. These results suggest that camptothecin may cause cell death in SiHa cells by inducing changes in mitochondrial membrane permeability, which leads to cytochrome c release and activation of caspase-3. This effect is also associated with increased formation of reactive oxygen species and depletion of GSH. Combination with other anticancer drugs (or signaling inhibitors) does not appear to increase the anti-tumor effect of camptothecin against SiHa cells, but rather may reduce it. Combination of camptothecin with other anticancer drugs does not seem to provide a benefit in the treatment of cervical and uterine cancer compared with camptothecin monotherapy.

Keywords

References

  1. Ackermann S, Beckmann MW, Thiel F, Bogenrieder T. Topotecan in cervical cancer. Int J Gynecol Cancer 17: 1215−1223, 2007 https://doi.org/10.1111/j.1525-1438.2007.01003.x
  2. Arbuck SG, Takimoto CH. An overview of topoisomerase I-targeting agents. Semin Hematol 35 Suppl 4: 3−12, 1998
  3. Armstrong JS. Mitochondria: a target for cancer therapy. Br J Pharmacol 147: 239−248, 2006 https://doi.org/10.1038/sj.bjp.0706556
  4. Berthier A, Lemaire-Ewing S, Prunet C, Monier S, Athias A, Bessede G, Pais de Barros JP, Laubriet A, Gambert P, Nèel D. Involvement of a calcium-dependent dephosphorylation of BAD associated with the localization of Trpc-1 within lipid rafts in 7-ketocholesterol-induced THP-1 cell apoptosis. Cell Death Differ 11: 97−905, 2004 https://doi.org/10.1038/sj.cdd.4401403
  5. Blum R, Jacob-Hirsch J, Rechavi G, Kloog Y. Suppression of survivin expression in glioblastoma cells by the Ras inhibitor farnesylthiosalicylic acid promotes caspase-dependent apoptosis. Mol Cancer Ther 5: 2337−2347, 2006 https://doi.org/10.1158/1535-7163.MCT-06-0193
  6. Brown GC. Nitric oxide and mitochondrial respiration. Biochim Biophys Acta 1411: 351−369, 1999 https://doi.org/10.1016/S0005-2728(99)00025-0
  7. Chandra J, Samali A, Orrenius S. Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 29: 323−333, 2000 https://doi.org/10.1016/S0891-5849(00)00302-6
  8. Chang F, Steelman LS, Shelton JG, Lee JT, Navolanic PM, Blalock WL, Franklin R, McCubrey JA. Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway. Int J Oncol 22: 469−480, 2003
  9. Constantini PC, Chernyak BC, Petronilli V, Bernardi P. Modulation of the mitochondrial permeability transition pore by pyridine nucleotides and dithiol oxidation at two separate sites. J Biol Chem 271: 6746−6751, 1996 https://doi.org/10.1074/jbc.271.12.6746
  10. Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res 95: 957−970, 2004 https://doi.org/10.1161/01.RES.0000148632.35500.d9
  11. Dias N, Bailly C. Drugs targeting mitochondrial functions to control tumor cell growth. Biochem Pharmacol 70: 1−12, 2005 https://doi.org/10.1016/j.bcp.2005.03.021
  12. Faivre S, Djelloul S, Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol 33: 407−420, 2006 https://doi.org/10.1053/j.seminoncol.2006.04.005
  13. Ferreira CG, Span SW, Peters GJ, Kruyt FA, Giaccone G. Chemotherapy triggers apoptosis in a caspase-8-dependent and mitochondria-controlled manner in the non-small cell lung cancer cell line NCI-H460. Cancer Res 60: 7133−7141, 2000
  14. Fleury C, Mignotte B, Vayssiere JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 84: 131−141, 2002 https://doi.org/10.1016/S0300-9084(02)01369-X
  15. Fu W, Luo H, Parthasarathy S, Mattson MP. Catecholamines potentiate amyloid β-peptide neurotoxicity: involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis. Neurobiol Dis 5: 229−243, 1998 https://doi.org/10.1006/nbdi.1998.0192
  16. Hall AG. The role of glutathione in the regulation of apoptosis. Eur J Clin Invest 29: 238−245, 1999 https://doi.org/10.1046/j.1365-2362.1999.00447.x
  17. Hong JS, Ko HH, Han ES, Lee CS. Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol. Biochem Pharmacol 66: 1297−1306, 2003 https://doi.org/10.1016/S0006-2952(03)00448-9
  18. Huang X, Kurose A, Tanaka T, Traganos F, Dai W, Darzynkiewicz Z. Activation of ATM and histone H2AX phosphorylation induced by mitoxantrone but not by topotecan is prevented by the antioxidant N-acetyl-L-cysteine. Cancer Biol Ther 5: 959−964, 2006 https://doi.org/10.4161/cbt.5.8.2878
  19. Kim R, Emi M, Tanabe K. Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 57: 545−553, 2006 https://doi.org/10.1007/s00280-005-0111-7
  20. Kobayashi T, Sawa H, Morikawa J, Jhang W, Shiku H. Bax induction activates apoptotic cascade via mitochondrial cytochrome c release and Bax overexpression enhances apoptosis induced by chemotherapeutic agents in DLD-1 colon cancer cells. Jpn J Cancer Res 91: 1264−1268, 2000 https://doi.org/10.1111/j.1349-7006.2000.tb00913.x
  21. Lee CS, Kim YJ, Lee MS, Han ES, Lee SJ. $18\beta$-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Life Sci 83: 481−489, 2008 https://doi.org/10.1016/j.lfs.2008.07.014
  22. Lee CS, Park SY, Ko HH, Han ES. Effect of change in cellular GSH levels on mitochondrial damage and cell viability loss due to mitomycin c in small cell lung cancer cells. Biochem Pharmacol 68: 1857−1867, 2004 https://doi.org/10.1016/j.bcp.2004.06.010
  23. Mignotte B, Vayssière JL. Mitochondria and apoptosis. Eur J Biochem 252: 1−15, 1998 https://doi.org/10.1046/j.1432-1327.1998.2520001.x
  24. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55−63, 1983 https://doi.org/10.1016/0022-1759(83)90303-4
  25. Nitiss JL, Wang JC. Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol Pharmacol 50: 1095−1102, 1996
  26. Pirnia F, Schneider E, Betticher DC, Borner M. Mitomycin c induces apoptosis and caspase-8 and -9 processing through a caspase-3 and Fas-independent pathway. Cell Death Differ 9: 905−914, 2002 https://doi.org/10.1038/sj.cdd.4401062
  27. Porter SE, Champoux JJ. The basis for camptothecin enhancement of DNA breakage by eukaryotic topoisomerase I. Nucleic Acids Res 17: 8521−8532, 1989 https://doi.org/10.1093/nar/17.21.8521
  28. Pritsos CA, Briggs LA, Gustafson DL. A new cellular target for mitomycin c: a case for mitochondrial DNA. Oncol Res 9: 333−337, 1997
  29. Sane AT, Cantin AM, Paquette B, Wagner JR. Ascorbate modulation of $H_{2}O_{2}$ and camptothecin-induced cell death in Jurkat cells. Cancer Chemother Pharmacol 54: 315−321, 2004
  30. Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y. Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA: DNA-PK complexes. EMBO J 18: 1397−1406, 1999 https://doi.org/10.1093/emboj/18.5.1397
  31. Timur M, Akbas SH, Ozben T. The effect of Topotecan on oxidative stress in MCF-7 human breast cancer cell line. Acta Biochim Pol 52: 897−902, 2005
  32. Tsao YP, Russo A, Nyamuswa G, Silber R, Liu LF. Interaction between replication forks and topoisomerase I-DNA cleavable complexes: studies in a cell-free SV40 DNA replication system. Cancer Res 53: 5908−5914, 1993
  33. Van Klaveren RJ, Hoet PHM, Pype JL, Demedts M, Nemery B. Increase in $\gamma$-glutamyltransferase by glutathione depletion in rat type II pneumocytes. Free Radic Biol Med 22: 525−534, 1997 https://doi.org/10.1016/S0891-5849(96)00375-9
  34. Wang P, Song JH, Song DK, Zhang J, Hao C. Role of death receptor and mitochondrial pathways in conventional chemotherapy drug induction of apoptosis. Cell Signal 18: 1528−1535, 2006 https://doi.org/10.1016/j.cellsig.2005.12.004
  35. Wenzel U, Nickel A, Kuntz S, Daniel H. Ascorbic acid suppresses drug-induced apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions. Carcinogenesis 25: 703−712, 2004 https://doi.org/10.1093/carcin/bgh079
  36. Xia S, Rosen EM, Laterra J. Sensitization of glioma cells to Fas-dependent apoptosis by chemotherapy-induced oxidative stress. Cancer Res 65: 5248−5255, 2005 https://doi.org/10.1158/0008-5472.CAN-04-4332
  37. Yang X, Zhang C, Ying M, Yang B, He Q. Antiproliferation in human EA.hy926 endothelial cells and inhibition of VEGF expression in PC-3 cells by topotecan. Pharmazie 62: 534−538, 2007