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Additive Interaction of Oxaliplatin and 17-Allylamino-17-demethoxygeldanamycin in Colon Cancer Cell Lines Results from Inhibition of Nuclear Factor B Signaling

Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania

Elucidation of the mechanism by which oxaliplatin induces cell death is essential to enhancing its action. We investigated the effects of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin (17-AAG) in a panel of four colon adenocarcinoma cell lines. Cytotoxicity assays demonstrated at least additivity in three of the cell lines. Activation of the c-Jun NH₂-terminal kinase pathway by oxaliplatin does not determine cytotoxicity. Activation of p38 was shown to be a key proapoptotic mediator of oxaliplatin-induced cell death. Modulation of extracellular signal-regulated kinase and AKT signaling had no impact on oxaliplatin toxicity in these cells. Nuclear factor (NF)-B was constitutively active in all of the cell lines and was inhibited by 17-AAG. Down-regulation of NF-B transactivation by pharmacological inhibitors enhanced oxaliplatin cytotoxicity. These data support an interaction between 17-AAG and components of the NF-B pathway in the modulation of oxaliplatin sensitivity in colon cancer cells.

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