2001年7月
Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol A on MRP1 function
INTERNATIONAL JOURNAL OF CANCER
- 巻
- 93
- 号
- 1
- 開始ページ
- 107
- 終了ページ
- 113
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1002/ijc.1290
- 出版者・発行元
- WILEY-LISS
We previously isolated agosterol A (AG-A) from a marine Spongio sp. and found that it completely reversed colchicine resistance in P-glycoprotein (Pgp)-over-expressing KB-C2 cells and vincristine resistance in multidrug-resistance protein (MRP)I -over-expressing CV60 cells. However, a tri-deacetylated derivative of AG-A (IAG-A) showed almost no activity in reversing Pgp- or MRP I-mediated drug resistance. In this study, we examined the mechanisms by which AG-A reverses MRP mediated drug resistance by investigating the interaction between agosterols and MRPI in MRPI-over-expressing human KB carcinoma (KB/MRP) cells. [H-3]-Leukotriene C, (LTC,), [H-3]-2,4-dinitrophenyl-S-glutathione uptake into membrane vesicles prepared from KB/MRP cells and intracellular [H-3]-vincristine accumulation and efflux in KB/MRP cells were measured with or without AG-A and/or inactive IAG-A. AG-A reduced MRPI-mediated [H-3]-LTC4 transport in a dose-dependent manner, but IAG-A did not. Inhibition by AG-A was competitive, with a K,value of 31 muM. AG-A at 10 muM enhanced the accumulation of [H-3]-vincristine in KB/MRP cells to the level of that in control cells in the absence of the agent. Likewise, ATP-dependent efflux of [H-3]-vincristine from KB/MRP cells was enhanced compared with KB-3-I cells and inhibited by AG-A. In addition, AG-A reduced intracellular levels of glutathione, a compound required for MRPI-mediated transport of some anti-cancer drugs. These findings suggest that AG-A reverses MRPI-mediated drug resistance by directly inhibiting the capacity of MRPI to transport drugs. In addition, the capacity of AG-A to reduce cellular glutathione levels may contribute to the modulating activity of MRPI. (C) 2001 Wiley-Liss, Inc.
- リンク情報
- ID情報
-
- DOI : 10.1002/ijc.1290
- ISSN : 0020-7136
- Web of Science ID : WOS:000168916900017