This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Judson, P. L. Articles by Haskill, J. S. Search for Related Content PubMed PubMed Citation Articles by Judson, P. L. Articles by Haskill, J. S.

Cisplatin Inhibits Paclitaxel-induced Apoptosis in Cisplatin-resistant Ovarian Cancer Cell Lines

Possible Explanation for Failure ofCombination Therapy¹

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology [P. L. J., P. A. G., W. C. F., J. S. H.], Lineberger Comprehensive Cancer Center [J. M. W., J. S. H.], University of North Carolina, Chapel Hill, North Carolina 27599-7295

Combination chemotherapy using paclitaxel with a platinum-based regimen is currently the standard first-line therapy for ovarian cancer after surgical cytoreduction. Whereas cisplatin-paclitaxel combination chemotherapy has shown significant efficacy over previous drug combinations in ovarian cancer, 20–30% of patients fail to respond to this combination. These patients are deemed cisplatin-paclitaxel resistant, although it is unclear whether the tumors are resistant to one or both drugs. Because the options available to ovarian cancer patients for second-line therapy are limited, and knowing that mechanistic differences exist between cisplatin and paclitaxel, we assessed the efficacy of combination drug therapy on cisplatin-resistant (cisplatin^R) ovarian cancer cells. We found that paclitaxel induced apoptosis in cisplatin^R cells as well as in the cisplatin-sensitive parental cell lines. In cisplatin^R C-13 cells, the concomitant addition of cisplatin blocked paclitaxel-induced apoptosis as determined by DNA fragmentation assays, fluorescence microscopy, and flow cytometry. Paclitaxel-induced multimininucleation was also inhibited when the cells were exposed sequentially to paclitaxel and then cisplatin. Cisplatin did not block paclitaxel-induced stabilization of microtubules or prevent paclitaxel-induced loss of Bcl-2 expression in cisplatin^R cells. Conversely, paclitaxel did not inhibit p53 protein accumulation by cisplatin. These results suggest that cisplatin blocks paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and independent of microtubule stabilization. Our research shows that cisplatin can inhibit the effectiveness of paclitaxel in cisplatin^R cell lines. Therefore, the establishment of a clinical protocol to evaluate the efficacy of paclitaxel alone versus another second-line regimen in patients with cisplatin-paclitaxel-resistant ovarian cancer is warranted.

This article has been cited by other articles:

				S. Zhang, C. Balch, M. W. Chan, H.-C. Lai, D. Matei, J. M. Schilder, P. S. Yan, T. H-M. Huang, and K. P. Nephew Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors Cancer Res., June 1, 2008; 68(11): 4311 - 4320. [Abstract] [Full Text] [PDF]

				D. Villa, M. Miloso, G. Nicolini, R. Rigolio, A. Villa, G. Cavaletti, and G. Tredici Low-dose cisplatin protects human neuroblastoma SH-SY5Y cells from paclitaxel-induced apoptosis Mol. Cancer Ther., September 1, 2005; 4(9): 1439 - 1447. [Abstract] [Full Text] [PDF]

				K. Anderson, K. A. Lawson, M. Simmons-Menchaca, L. Sun, B. G. Sanders, and K. Kline {alpha}-TEA Plus Cisplatin Reduces Human Cisplatin-Resistant Ovarian Cancer Cell Tumor Burden and Metastasis Exp Biol Med, December 1, 2004; 229(11): 1169 - 1176. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, B. Sweeney-Gotsch, R. Takamori, and D. J. McConkey The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts Mol. Cancer Ther., January 1, 2004; 3(1): 59 - 70. [Abstract] [Full Text]

				M. A. Bookman Developmental Chemotherapy and Management of Recurrent Ovarian Cancer J. Clin. Oncol., May 15, 2003; 21(90100): 149s - 167. [Abstract] [Full Text] [PDF]

				J. D. Wulfkuhle, D. C. Sgroi, H. Krutzsch, K. McLean, K. McGarvey, M. Knowlton, S. Chen, H. Shu, A. Sahin, R. Kurek, et al. Proteomics of Human Breast Ductal Carcinoma in Situ Cancer Res., November 15, 2002; 62(22): 6740 - 6749. [Abstract] [Full Text] [PDF]

				M. G. Cantu, A. Buda, G. Parma, R. Rossi, I. Floriani, C. Bonazzi, T. Dell'Anna, V. Torri, and N. Colombo Randomized Controlled Trial of Single-Agent Paclitaxel Versus Cyclophosphamide, Doxorubicin, and Cisplatin in Patients With Recurrent Ovarian Cancer Who Responded to First-Line Platinum-Based Regimens J. Clin. Oncol., March 1, 2002; 20(5): 1232 - 1237. [Abstract] [Full Text] [PDF]

				E. Auzenne, N. J. Donato, C. Li, E. Leroux, R. E. Price, D. Farquhar, and J. Klostergaard Superior Therapeutic Profile of Poly-L-Glutamic Acid-Paclitaxel Copolymer Compared with Taxol in Xenogeneic Compartmental Models of Human Ovarian Carcinoma Clin. Cancer Res., February 1, 2002; 8(2): 573 - 581. [Abstract] [Full Text] [PDF]

				M. A. Shah and G. K. Schwartz Cell Cycle-mediated Drug Resistance: An Emerging Concept in Cancer Therapy Clin. Cancer Res., August 1, 2001; 7(8): 2168 - 2181. [Abstract] [Full Text] [PDF]

				K.-C. Choi, S. K. Kang, C.-J. Tai, N. Auersperg, and P. C. K. Leung Estradiol Up-Regulates Antiapoptotic Bcl-2 Messenger Ribonucleic Acid and Protein in Tumorigenic Ovarian Surface Epithelium Cells Endocrinology, June 1, 2001; 142(6): 2351 - 2360. [Abstract] [Full Text] [PDF]

				K. Yamamoto, Y. Kikuchi, K. Kudoh, J. Hirata, T. Kita, and I. Nagata Treatment with Paclitaxel Alone Rather than Combination with Paclitaxel and Cisplatin May be Selective for Cisplatin-resistant Ovarian Carcinoma Jpn. J. Clin. Oncol., October 1, 2000; 30(10): 446 - 449. [Abstract] [Full Text] [PDF]