c-kit inhibitor masitinib induces reactive oxygen species-dependent apoptosis in c-kit-negative HepG2 cells.

Tumor-specific growth signal inhibition is a major anticancer strategy. Receptor tyrosine kinases (RTKs) are the most upstream receptors for growth signaling in cancer. Therefore, inhibition of RTKs has been proposed as an efficient therapeutic target. Masitinib, a c-kit inhibitor of the c-kit RTK, was developed to treat mastocytoma in dogs. In humans, however, the antitumor efficacy of masitinib was found to be attenuated against tumor cells with mutations of the c-kit gene. Here, we report that masitinib induced cell death via the intrinsic apoptotic pathway in HepG2, a c-kit-negative hepatocellular carcinoma cell line. In masitinib-treated HepG2 cells, increases in intracellular reactive oxygen species levels, loss of mitochondrial membrane potential, and cleavage of caspase-9 were observed, activating the intrinsic apoptotic pathway. Moreover, the cytotoxicity of masitinib to HepG2 cells was suppressed by treatment with the antioxidant N-acetyl-

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