Reversal of cisplatin resistance by the 1,4-benzothiazepine derivative, JTV-519

Abstract

The 1,4-benzothiazepine derivative JTV-519 is a new type of calcium ion channel modulator. We examined the modulatory effect of JTV-519 on the antitumor activity of several platinum compounds (cisplatin, carboplatin, and nedaplatin) in a human cancer cell line resistant to cisplatin (PC-14/CDDP) in vitro. PC-14/CDDP cells showed 8-fold resistance to cisplatin compared with the parental PC-14 cells as determined by dye formation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] assay. In PC-14/CDDP, but not PC-14 cells, augmentation of cytotoxicity was observed when a nontoxic concentration (10 μM) of JTV-519 was combined with the platinum compounds. Increased intracellular cisplatin accumulation was observed in PC-14/CDDP cells in the presence of JTV-519 as measured by atomic absorption assay. Therefore, increased cisplatin accumulation was considered to be a possible mechanism underlying the reversing effect of JTV-519 on cisplatin resistance. These results suggest that JTV-519 is a potent agent reversing cisplatin resistance.