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Effects of Various Methoxyflavones on Vincristine Uptake and Multidrug Resistance to Vincristine in P-gp-Overexpressing K562/ADM Cells

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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.

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Authors and Affiliations

  1. Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Hisakazu Ohtani & Yasufumi Sawada

  2. Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Tomomi Ikegawa & Youko Honda

  3. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan

    Noriko Kohyama

  4. Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Satoshi Morimoto &  Yukihiro Shoyama

  5. Faculty of Pharmaceutical Sciences, Mukogawa Women’s University, Nishinomiya, Hyogo, 663-8179, Japan

    Motoharu Juichi

  6. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi, Bunkyo-ku, 113-0032, Japan

    Mikihiko Naito & Takashi Tsuruo

Authors
  1. Hisakazu Ohtani
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  2. Tomomi Ikegawa
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  3. Youko Honda
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  4. Noriko Kohyama
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  5. Satoshi Morimoto
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  7. Motoharu Juichi
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  8. Mikihiko Naito
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  9. Takashi Tsuruo
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  10. Yasufumi Sawada
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Correspondence to Yasufumi Sawada.

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Ohtani, H., Ikegawa, T., Honda, Y. et al. Effects of Various Methoxyflavones on Vincristine Uptake and Multidrug Resistance to Vincristine in P-gp-Overexpressing K562/ADM Cells. Pharm Res 24, 1936–1943 (2007). https://doi.org/10.1007/s11095-007-9320-6

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  • DOI: https://doi.org/10.1007/s11095-007-9320-6

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