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

研究成果: Article査読

37 被引用数 (Scopus)

抄録

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 3μM reversed the resistance of K562/MDR cells to vincristine (VCR), taxol, etoposide (VP16), adriamycin (ADM) and actinomycin D and at 0.5 or 1μM reversed their resistance to STI571. JTV-519 at 10μM 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 500μM JTV-519. JTV-519 at 3μM also partially reversed the resistance of KB/MRP cells to VCR and at 500μM partially inhibited the photoaffinity labeling of MRP1 with 125I-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.

本文言語English
ページ(範囲)111-119
ページ数9
ジャーナルCancer Letters
187
1-2
DOI
出版ステータスPublished - 2002 12月 10
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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