Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells

Hisakazu Ohtani, Tomomi Ikegawa, Youko Honda, Noriko Kohyama, Satoshi Morimoto, Yukihiro Shoyama, Motoharu Juichi, Mikihiko Naito, Takashi Tsuruo, Yasufumi Sawada

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Purpose. Some methoxyflavones (MFs) are known to inhibit the function of P-glycoprotein. The aim of this study is to characterize the reversal of multidrug resistance (MDR) by MFs. Methods. The effects of 19 MFs, including 3,5,6,7,8,3′,4′-heptamethoxyflavone, nobiletin, and tangeretin, and flavone on the uptake of [3H]vincristine into an adriamycin-resistant variant of human chronic myelogenous leukemia (K562/ADM) cells were investigated. Potentiation of vincristine-induced growth inhibition by these MFs was also tested in K562/ADM cells by means of WST-1 [2-(4-iodophenyl)-3-(4- nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] assay. Results. All MFs (20 μM) tested increased the uptake of [3H]vincristine. 3,5,6,7,8,3′,4′-heptamethoxyflavone, nobiletin, tangeretin, quercetagetin and quercetin pentamethylether showed especially potent effects. The increase in the uptake of [3H]vincristine was proportional to the number of methoxyl moieties. While substitution with a methoxyl moiety at the C3 position was the most influential, methoxyl substitution at both the C3′ and C5′ positions resulted in a decrease in the potentiation of uptake. Furthermore, there was a significant correlation between the potencies for increasing [3H]vincristine uptake and for growth inhibition assessed by WST-1 assay. Conclusions. MFs increased the uptake of [ 3H]vincristine into MDR cells and exhibited MDR-reversing effects. Their potencies were influenced by the number and positions of the methoxyl moieties.

Original languageEnglish
Pages (from-to)1936-1943
Number of pages8
JournalPharmaceutical research
Volume24
Issue number10
DOIs
Publication statusPublished - 2007 Oct
Externally publishedYes

Keywords

  • Methoxyflavone
  • Multidrug resistance
  • P-glycoprotein
  • Structure-activity relationship

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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