Metabolism of thalidomide by human liver microsome cytochrome CYP2C19 is required for its antimyeloma and antiangiogenic activitiesin vitro

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In this study, we used a system of human liver microsomes to investigate the antimyeloma and antiangiogenic activities of thalidomide. Myeloma cells and human umbilical vein endothelial cells (HUVECs) were treated with thalidomide alone or thalidomide incubated with human liver microsomal protein. We found that thalidomide alone had no direct effect on several multiple myeloma cell lines (U266, NCI-H929, RPMI 8226, LP-1, CZ-1) or on HUVECsin vitro. However, when incubated with human liver microsomal protein, thalidomide (100 μg/ml) caused a decrease of 34.9–46.7% in cell viability in myeloma cells and 12% in HUVECs. Cell cycle analysis and apoptosis detection indicated that the decreases in cell viability were correlated with the induction of apoptosis. Thalidomide incubated with microsomal protein also influenced HUVEC migration and tube formation. These effects were partially reversed by omeprazole (10 μmol/l), a potent inhibitor of CYP2C19, suggesting that CYP2C19 is required for thalidomide to exhibit its antimyeloma and antiangiogenic activities.

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