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

doi:10.1016/S0304-3835(02)00359-2

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 journal › Article › peer-review

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 language	English
Pages (from-to)	111-119
Number of pages	9
Journal	Cancer Letters
Volume	187
Issue number	1-2
DOIs	https://doi.org/10.1016/S0304-3835(02)00359-2
Publication status	Published - 2002 Dec 10
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S0304-3835(02)00359-2

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@article{dac75b885ce54966859c820472d821ee,

title = "Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519",

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.",

keywords = "JTV-519, Multidrug resistance, Multidrug resistance protein 1, P-glycoprotein",

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

note = "Funding Information: This work was supported by grants from the Heiwa Nakajima Foundation, Japan. We thank Japan Tobacco Co. for offering JTV-519. We also thank Ms Etsuko Sudou for technical assistance and Ms Hiromi Kakura for secretarial assistance.",

year = "2002",

month = dec,

day = "10",

doi = "10.1016/S0304-3835(02)00359-2",

language = "English",

volume = "187",

pages = "111--119",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "Elsevier Ireland Ltd",

number = "1-2",

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TY - JOUR

T1 - Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519

AU - Che, Xiao Fang

AU - Nakajima, Yuichi

AU - Sumizawa, Tomoyuki

AU - Ikeda, Ryuji

AU - Ren, Xiao Qin

AU - Zheng, Chun Lei

AU - Mukai, Motoi

AU - Furukawa, Tatsuhiko

AU - Haraguchi, Misako

AU - Gao, Hui

AU - Sugimoto, Yoshikazu

AU - Akiyama, Shin ichi

N1 - Funding Information: This work was supported by grants from the Heiwa Nakajima Foundation, Japan. We thank Japan Tobacco Co. for offering JTV-519. We also thank Ms Etsuko Sudou for technical assistance and Ms Hiromi Kakura for secretarial assistance.

PY - 2002/12/10

Y1 - 2002/12/10

N2 - 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.

AB - 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.

KW - JTV-519

KW - Multidrug resistance

KW - Multidrug resistance protein 1

KW - P-glycoprotein

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U2 - 10.1016/S0304-3835(02)00359-2

DO - 10.1016/S0304-3835(02)00359-2

M3 - Article

C2 - 12359358

AN - SCOPUS:17744421180

SN - 0304-3835

VL - 187

SP - 111

EP - 119

JO - Cancer Letters

JF - Cancer Letters

IS - 1-2

ER -

Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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