Radiosensitization of Human Mammary Carcinoma Cells by Specific Inhibition of Signal Transduction Cascades
Annual summary rept. 1 Aug 2001-31 Jul 2002
VIRGINIA COMMONWEALTH UNIV RICHMOND
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We investigated the impact of combined exposure to the check-point abrogator UCN-01 in conjunction with MEK12 inhibitors upon survival of mammary carcinoma cells. Treatment of cells with UCN-01 resulted in prolonged activation of the MAPK pathway. Inhibition of MEK12 caused modest reductions in basal MAPK activity and suppressed UCN-01-stimulated MAPK activity below that of MEK12 inhibitor alone. Significantly, combined, but not individual, exposure of cells to UCN-01 and MEK12 inhibitors enhanced BAX association with mitochondria and triggered release of cytochrome c into the cytosol, accompanied by activation of effector pro-caspases, resulting in a synergistic potentiation of apoptosis within 18-24th. Radiation exposure of drug treated cells did not further enhance apoptosis. Treatment of cells with both caspase 9 and caspase 8 inhibitors was required to completely inhibit apoptosis in carcinoma cells.
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