This Article Full Text Full Text (PDF) Alert me when this article is cited 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.

Geldanamycin and its 17-Allylamino-17-Demethoxy Analogue Antagonize the Action of Cisplatin in Human Colon Adenocarcinoma Cells

Differential Caspase Activation as a Basis for Interaction¹

University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104

Several chaperone-binding drugs based on geldanamycin (GA) have been synthesized, and one of them, 17-allylamino-17-demethoxygeldanamycin (17-AAG), is being developed in the clinic. Interest in the use of 17-AAG in combination with cytotoxic drugs led us to study both GA and 17-AAG with cisplatin (DDP) in the human colon adenocarcinoma cell lines HT29 and HCT116. We performed isobologram analysis of combinations of DDP with GA or 17-AAG in these cell lines using the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to evaluate cell survival. In HCT116, the effects of GA and 17-AAG with DDP were additive and schedule dependent. In HT29 both GA and 17-AAG antagonized DDP effects resulting in cytotoxicity less than expected. We hypothesized that the antagonism in HT29 cells might be a consequence of altered p53 function in this cell line. Accordingly, we tested GA/17-AAG and DDP in combination in the HCTp5.2 cell line, which expresses a dominant-negative form of p53. In these cells too, the GA analogues antagonized DDP, suggesting a role for p53 in the observed effects. Investigation of the DDP-induced signaling pathways revealed that ansamycins block the activation of mitogen-activated protein kinase and c-Jun NH₂-terminal kinase pathways and c-Jun expression in HT29 cells while exerting incomplete inhibitory effects in HCT116 and HCTp5.2 cell lines. Therefore, effects on signaling are thought not to underlay the antagonism in the latter model. The ansamycins inhibited DDP-induced activation of caspases 8 and 3 in HT29 and HCTp5.2 but not in HCT116 cells, which we postulate to be the basis for higher survival of p53-deficient cells when treated with combinations of the two drugs.

This article has been cited by other articles:

				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]

				A. I. Robles, M. H. Wright, B. Gandhi, S. S. Feis, C. L. Hanigan, A. Wiestner, and L. Varticovski Schedule-Dependent Synergy between the Heat Shock Protein 90 Inhibitor 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin and Doxorubicin Restores Apoptosis to p53-Mutant Lymphoma Cell Lines. Clin. Cancer Res., November 1, 2006; 12(21): 6547 - 6556. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, J. S. Carew, M. S. Pino, R. A. Highshaw, K. Dunner Jr., P. Huang, J. L. Abbruzzese, and D. J. McConkey Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis Cancer Res., December 15, 2005; 65(24): 11658 - 11666. [Abstract] [Full Text] [PDF]

				P. Muller, P. Ceskova, and B. Vojtesek Hsp90 Is Essential for Restoring Cellular Functions of Temperature-sensitive p53 Mutant Protein but Not for Stabilization and Activation of Wild-type p53: IMPLICATIONS FOR CANCER THERAPY J. Biol. Chem., February 25, 2005; 280(8): 6682 - 6691. [Abstract] [Full Text] [PDF]

				R. Bagatell and L. Whitesell Altered Hsp90 function in cancer: A unique therapeutic opportunity Mol. Cancer Ther., August 1, 2004; 3(8): 1021 - 1030. [Abstract] [Full Text] [PDF]

				I. A. Vasilevskaya, T. V. Rakitina, and P. J. O'Dwyer 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 Mol. Pharmacol., January 1, 2004; 65(1): 235 - 243. [Abstract] [Full Text] [PDF]

				T. V. Rakitina, I. A. Vasilevskaya, and P. J. O'Dwyer Additive Interaction of Oxaliplatin and 17-Allylamino-17-demethoxygeldanamycin in Colon Cancer Cell Lines Results from Inhibition of Nuclear Factor {kappa}B Signaling Cancer Res., December 15, 2003; 63(24): 8600 - 8605. [Abstract] [Full Text] [PDF]