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 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 mM) 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.
Nakamura
T
T
Pharmacology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Koizumi
F
F
Kaneko
N
N
Tamura
T
T
Chiwaki
F
F
Koh
Y
Y
Akutagawa
S
S
Saijo
N
N
Nishio
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy; D008956:Models, Chemical; D009944:Organoplatinum Compounds / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D009944:Organoplatinum Compounds; D013841:Thiazepines; C109183:K201 compound; C053989:nedaplatin; D016190:Carboplatin; D002945:Cisplatin