QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services 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 Vasilevskaya, I. A. Articles by O'Dwyer, P. J. Search for Related Content PubMed PubMed Citation Articles by Vasilevskaya, I. A. Articles by O'Dwyer, P. J.

Quantitative Effects on c-Jun N-Terminal Protein Kinase Signaling Determine Synergistic Interaction of Cisplatin and 17-Allylamino-17-Demethoxygeldanamycin in Colon Cancer Cell Lines

University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania

We investigated the effects of cisplatin and the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination in a panel of human colon adenocarcinoma cell lines that differ in their p53 and mismatch repair status. Analysis of cytotoxicity after combined treatment revealed additive effects of cisplatin and 17-AAG in the HCT 116, DLD1, and SW480 cell lines and antagonism in HT-29 cells. Clonogenic assays demonstrated antagonism in HT-29, an additive effect in SW480, and synergism in HCT 116 and DLD1 cell lines. Analysis of signaling pathways revealed that cisplatin-induced activation of c-Jun N-terminal kinase (JNK) was fully blocked by 17-AAG in HT-29 and SW480 cells, whereas in HCT 116 and DLD1 cells it was inhibited only partially. The activation of caspases was also more pronounced in DLD1 and HCT 116 cell lines. These data suggested that a minimal level of apoptotic signaling through JNK was required for synergism with this combination. To test this hypothesis, we used the specific JNK inhibitor SP600125; when JNK was inhibited pharmacologically in HCT 116 and DLD1 cells, they demonstrated increased survival in clonogenic assays. Alternatively, sustained activation of JNK pathway led to an increase of the cytotoxicity of the cisplatin/17-AAG combination in HT-29 cells. Taken together, these data suggest that the synergistic interaction of this combination in colon cancer cell lines depends on the effect exerted by 17-AAG on cisplatin-induced signaling through JNK and associated pathways leading to cell death. An implication of that finding is that quantitative effects of signaling inhibitors may be critical for their ability to reverse cisplatin resistance.

Received July 24, 2003; accepted October 10, 2003.

Address correspondence to: Dr. Irina A. Vasilevskaya, University of Pennsylvania, 1020 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: vasilevs{at}mail.med.upenn.edu

This article has been cited by other articles:

				S. Fernandez de Mattos, P. Villalonga, J. Clardy, and E. W-F. Lam FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells Mol. Cancer Ther., October 1, 2008; 7(10): 3237 - 3246. [Abstract] [Full Text] [PDF]

				C. Peklak-Scott, P. K. Smitherman, A. J. Townsend, and C. S. Morrow Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin Mol. Cancer Ther., October 1, 2008; 7(10): 3247 - 3255. [Abstract] [Full Text] [PDF]

				A. K. McCollum, K. B. Lukasiewicz, C. J. TenEyck, W. L. Lingle, D. O. Toft, and C. Erlichman Cisplatin abrogates the geldanamycin-induced heat shock response Mol. Cancer Ther., October 1, 2008; 7(10): 3256 - 3264. [Abstract] [Full Text] [PDF]

				I. A. Vasilevskaya, M. Selvakumaran, and P. J. O'Dwyer Disruption of Signaling through SEK1 and MKK7 Yields Differential Responses in Hypoxic Colon Cancer Cells Treated with Oxaliplatin Mol. Pharmacol., July 1, 2008; 74(1): 246 - 254. [Abstract] [Full Text] [PDF]

				H. D. C. Francescato, R. S. Costa, F. B. Junior, and T. M. Coimbra Effect of JNK inhibition on cisplatin-induced renal damage Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2138 - 2148. [Abstract] [Full Text] [PDF]

				Y. Matsui, S. Ueda, J. Watanabe, I. Kuwabara, O. Ogawa, and H. Nishiyama Sensitizing Effect of Galectin-7 in Urothelial Cancer to Cisplatin through the Accumulation of Intracellular Reactive Oxygen Species Cancer Res., February 1, 2007; 67(3): 1212 - 1220. [Abstract] [Full Text] [PDF]

				N. Sain, B. Krishnan, M. G. Ormerod, A. De Rienzo, W. M. Liu, S. B. Kaye, P. Workman, and A. L. Jackman Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT Mol. Cancer Ther., May 1, 2006; 5(5): 1197 - 1208. [Abstract] [Full Text] [PDF]

				E. Schmitt, L. Maingret, P.-E. Puig, A.-L. Rerole, F. Ghiringhelli, A. Hammann, E. Solary, G. Kroemer, and C. Garrido Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res., April 15, 2006; 66(8): 4191 - 4197. [Abstract] [Full Text] [PDF]

				X. Wang, W. Ju, J. Renouard, J. Aden, S. A. Belinsky, and Y. Lin 17-Allylamino-17-Demethoxygeldanamycin Synergistically Potentiates Tumor Necrosis Factor-Induced Lung Cancer Cell Death by Blocking the Nuclear Factor-{kappa}B Pathway Cancer Res., January 15, 2006; 66(2): 1089 - 1095. [Abstract] [Full Text] [PDF]