17-Allylamino-17-demethoxygeldanamycin overcomes TRAIL resistance in colon cancer cell lines |
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Authors: | Vasilevskaya Irina A O'Dwyer Peter J |
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Institution: | University of Pennsylvania Cancer Center, 1020 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA. vasilevs@mail.med.upenn.edu |
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Abstract: | Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising candidate for treatment of cancer, but displays variable cytotoxicity in cell lines. The mechanisms of sensitivity and resistance have not been fully elucidated; both AKT and NF-kappaB pathways may modulate cytotoxic responses. We have shown that the Hsp90 inhibitor 17-AAG enhances the cytotoxicity of oxaliplatin in colon cancer cell lines through inhibition of NF-kappaB. We analyzed the effects of TRAIL and 17-AAG in combination in a series of nine colon cancer cell lines and characterized activation of the pathways to apoptosis. IC(50) values for a 72 h exposure to TRAIL ranged from 30 to 4000 ng/ml. Cytotoxicity assays demonstrated additivity or synergism of the TRAIL/17-AAG combination in all cell lines, with combination indices at IC(50) ranging from 0.53 to 1. The sensitizing effect of 17-AAG was greater in the TRAIL-resistant cell lines. In TRAIL-resistant cell lines, the combination of 17-AAG and TRAIL resulted in activation of both extrinsic and intrinsic apoptotic pathways, though with quantitative differences between HT29 and RKO cells: differential effects of 17-AAG on AKT and NF-kappaB characterized these cell lines. In both cell lines, the combination also led to down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and enhanced activation of caspase-3. We conclude that either AKT or NF-kappaB may promote resistance to TRAIL in colon cancer cells, and that the ability of 17-AAG to target multiple putative determinants of TRAIL sensitivity warrants their further investigation in combination. |
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Keywords: | hsp90 90 kDa heat-shock protein 17-AAG 17-allylamino-17-demethoxygeldanamycin TRAIL tumor necrosis factor-related apoptosis-inducing ligand DR4 and DR5 death receptors 4 and 5 respectively CI combination index DISC death-inducing signaling complex FLIP FLICE inhibitory protein c-IAP1/2 cellular inhibitors of apoptosis 1/2 XIAP X-linked IAP AIF apoptosis-inducing factor AP-1 activator-protein 1 NF-κB nuclear factor kappa B MTT 3-(4 5-dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide |
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