Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein

Nobuya Kusunoki, Kohji Takara, Yusuke Tanigawara, Aiko Yamauchi, Kazumitsu Ueda, Fusao Komada, Yonson Ku, Yoshikazu Kuroda, Yohichi Saitoh, Katsuhiko Okumura

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50%-inhibitory concentration (IC 50) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 μM, respectively, and those for vinblastine transport were 1.06 and 5.10 μM, respectively. The IC 50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than that of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.

Original languageEnglish
Pages (from-to)1220-1228
Number of pages9
JournalJapanese Journal of Cancer Research
Volume89
Issue number11
Publication statusPublished - 1998

Fingerprint

Vinblastine
P-Glycoprotein
Doxorubicin
Cyclosporine
valspodar
Transcytosis
Inhibitory Concentration 50

Keywords

  • Cyclosporin A
  • Multidrug resistance
  • P-glycoprotein
  • SDZ PSC 833

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein. / Kusunoki, Nobuya; Takara, Kohji; Tanigawara, Yusuke; Yamauchi, Aiko; Ueda, Kazumitsu; Komada, Fusao; Ku, Yonson; Kuroda, Yoshikazu; Saitoh, Yohichi; Okumura, Katsuhiko.

In: Japanese Journal of Cancer Research, Vol. 89, No. 11, 1998, p. 1220-1228.

Research output: Contribution to journalArticle

Kusunoki, N, Takara, K, Tanigawara, Y, Yamauchi, A, Ueda, K, Komada, F, Ku, Y, Kuroda, Y, Saitoh, Y & Okumura, K 1998, 'Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein', Japanese Journal of Cancer Research, vol. 89, no. 11, pp. 1220-1228.
Kusunoki, Nobuya ; Takara, Kohji ; Tanigawara, Yusuke ; Yamauchi, Aiko ; Ueda, Kazumitsu ; Komada, Fusao ; Ku, Yonson ; Kuroda, Yoshikazu ; Saitoh, Yohichi ; Okumura, Katsuhiko. / Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein. In: Japanese Journal of Cancer Research. 1998 ; Vol. 89, No. 11. pp. 1220-1228.
@article{cddb73123ab7481496641fe704bd1dc4,
title = "Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein",
abstract = "The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50{\%}-inhibitory concentration (IC 50) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 μM, respectively, and those for vinblastine transport were 1.06 and 5.10 μM, respectively. The IC 50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than that of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.",
keywords = "Cyclosporin A, Multidrug resistance, P-glycoprotein, SDZ PSC 833",
author = "Nobuya Kusunoki and Kohji Takara and Yusuke Tanigawara and Aiko Yamauchi and Kazumitsu Ueda and Fusao Komada and Yonson Ku and Yoshikazu Kuroda and Yohichi Saitoh and Katsuhiko Okumura",
year = "1998",
language = "English",
volume = "89",
pages = "1220--1228",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "11",

}

TY - JOUR

T1 - Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein

AU - Kusunoki, Nobuya

AU - Takara, Kohji

AU - Tanigawara, Yusuke

AU - Yamauchi, Aiko

AU - Ueda, Kazumitsu

AU - Komada, Fusao

AU - Ku, Yonson

AU - Kuroda, Yoshikazu

AU - Saitoh, Yohichi

AU - Okumura, Katsuhiko

PY - 1998

Y1 - 1998

N2 - The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50%-inhibitory concentration (IC 50) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 μM, respectively, and those for vinblastine transport were 1.06 and 5.10 μM, respectively. The IC 50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than that of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.

AB - The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50%-inhibitory concentration (IC 50) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 μM, respectively, and those for vinblastine transport were 1.06 and 5.10 μM, respectively. The IC 50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than that of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.

KW - Cyclosporin A

KW - Multidrug resistance

KW - P-glycoprotein

KW - SDZ PSC 833

UR - http://www.scopus.com/inward/record.url?scp=20244370494&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20244370494&partnerID=8YFLogxK

M3 - Article

VL - 89

SP - 1220

EP - 1228

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

IS - 11

ER -