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Reversal of P-glycoprotein Mediated Multidrug Resistance by a Newly Synthesized 1,4-benzothiazipine Derivative, JTV-519

Reversal of P-glycoprotein Mediated Multidrug Resistance by a Newly Synthesized 1,4-benzothiazipine Derivative, JTV-519

Xiao-Fang Che, Yuichi Nakajima, Tomoyuki Sumizawa, Ryuji Ikeda, Xiao-Qin Ren, Chun-Lei Zheng, Motoi Mukai, Tatsuhiko Furukawa, Misako Haraguchi, Hui Gao, Yoshikazu Sugimoto, Shin-ichi Akiyama

Cancer Lett. 2002 Dec 10;187(1-2):111-9.

PMID: 12359358

Abstract:

A newly synthesized 1,4-benzothiazipine derivate, 4-[3-(4-benzylpiperidin-1-yl) propionyl]-7-methoxy-2,3,4,5-tetrahydro-1, 4-benzothiazepine monohydrochloride (JTV-519) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1) mediated multidrug resistance (MDR) in K562/MDR and KB/MRP cells, respectively. JTV-519 at 3 microM reversed the resistance of K562/MDR cells to vincristine (VCR), taxol, etoposide (VP16), adriamycin (ADM) and actinomycin D and at 0.5 or 1 microM reversed their resistance to STI571. JTV-519 at 10 microM enhanced the accumulation of ADM in K562/MDR cells to the level in parental K562 cells and inhibited the efflux of ADM from K562/MDR cells. Photoaffinity labeling of P-gp with 3H-azidopine was almost completely inhibited by 500 microM JTV-519. JTV-519 at 3 microM also partially reversed the resistance of KB/MRP cells to VCR and at 500 microM partially inhibited the photoaffinity labeling of MRP1 with (125)I-II-azidophenyl agosterol A (125I-azidoAG-A). These results suggest that JTV-519 reversed the resistance to the anti-cancer agents in P-gp and MRP1 overexpressing multidrug-resistant cells by directly binding to P-gp and MRP1, and competitively inhibiting transport of the anti-cancer agents.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP145903066	4-[3-(4-Benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine		145903-06-6	Price
AP927871769	2,3,4,5-Tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine		927871-76-9	Price

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