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

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)111-119
Number of pages9
JournalCancer Letters
Volume187
Issue number1-2
DOIs
Publication statusPublished - 2002 Dec 10
Externally publishedYes

Keywords

  • JTV-519
  • Multidrug resistance
  • Multidrug resistance protein 1
  • P-glycoprotein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Che, X. F., Nakajima, Y., Sumizawa, T., Ikeda, R., Ren, X. Q., Zheng, C. L., Mukai, M., Furukawa, T., Haraguchi, M., Gao, H., Sugimoto, Y., & Akiyama, S. I. (2002). Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519. Cancer Letters, 187(1-2), 111-119. https://doi.org/10.1016/S0304-3835(02)00359-2