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

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49 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 (IC50) 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 IC50 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
DOIs
Publication statusPublished - 1998 Jan 1

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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