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Bay 43-9006 is an inhibitor of RAF kinases that has been shown to inhibit proliferation and to induce apoptosis of cancer cells. Oncogenes KRAS or BRAF are frequently mutated in colon cancer. By using a panel of colon cancer cell lines, we showed that Bay 43-9006 was capable of growth inhibition and inducing cell death, correlated with the inhibition of ERK phosphorylation, irrespective of mutation status of KRAS or BRAF. Examination of the cell death revealed both caspase-dependent apoptosis in HCT116 and caspase-independent autophagy in HT29. The autophagic cell death induced by Bay 43-9006 was insensitive to a pan-caspase inhibitor Z-VAD-FMK. It was associated with the accumulation of autophagosomes and the punctate localization of an autophagic marker, LC3. The Bay 43-9006-induced autophagy might be a general phenomenon, as it also induced autophagy in HEK293 cells. While the autophagy induced by a high concentration of Bay 43-9006 was associated with cell death, at a lower but pharmacologically relevant concentration, it was correlated with growth inhibition. Our results further suggested that a lower level of Bay 43-9006 was capable of inducing autophagy associated with the inhibition of apoptosis and cell death induced by chemotherapy agent camptothecin.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA