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

The 1,4-benzothiazepine derivative JTV-519 is a new type of calcium ion cha nnel modulator. We examined the modulatory effect of JTV-519 on the antitum or activity of several platinum compounds (cisplatin, carboplatin, and neda platin) in a human cancer cell lint? resistant to cisplatin (PC-14/CDDP) in vitro. PC-14/CDDP cells showed 8-fold resistance to cisplatin compared wit h the parental PC-14 cells as determined by dye formation [3-(4,5-dimethylt hiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] assay. In PC-14/CDDF, bu t not PC-14 cells, augmentation of cytotoxicity was observed when a nontoxi c concentration (10 muM) of JTV-519 was combined with the platinum compound s, Increased intracellular cisplatin accumulation was observed in PC-14/CDD P 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 resistan ce. These results suggest that JTV-519 is a potent agent reversing cisplati n resistance.