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Chen ZS , Aoki S , Komatsu M , Ueda K , Sumizawa T , Furukawa T , Okumura H , Ren XQ , Belinsky MG , Lee K , Kruh GD , Kobayashi M , Akiyama S
Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol A on MRP1 function
Int J Cancer. 2001 Jul 1;93(1) :107-13
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We previously isolated agosterol A (AG-A) from a marine Spongia 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)1-over-expressing CV60 cells. However, a tri-deacetylated derivative of AG-A (IAG-A) showed almost no activity in reversing Pgp- or MRP1-mediated drug resistance. In this study, we examined the mechanisms by which AG-A reverses MRP1-mediated drug resistance by investigating the interaction between agosterols and MRP1 in MRP1-over-expressing human KB carcinoma (KB/MRP) cells. [3H]-Leukotriene C4 (LTC4), [3H]-2,4-dinitrophenyl-S-glutathione uptake into membrane vesicles prepared from KB/MRP cells and intracellular [3H]-vincristine accumulation and efflux in KB/MRP cells were measured with or without AG-A and/or inactive IAG-A. AG-A reduced MRP1-mediated [3H]-LTC4 transport in a dose-dependent manner, but IAG-A did not. Inhibition by AG-A was competitive, with a K(i) value of 31 microM. AG-A at 10 microM enhanced the accumulation of [3H]-vincristine in KB/MRP cells to the level of that in control cells in the absence of the agent. Likewise, ATP-dependent efflux of [3H]-vincristine from KB/MRP cells was enhanced compared with KB-3-1 cells and inhibited by AG-A. In addition, AG-A reduced intracellular levels of glutathione, a compound required for MRP1-mediated transport of some anti-cancer drugs. These findings suggest that AG-A reverses MRP1-mediated drug resistance by directly inhibiting the capacity of MRP1 to transport drugs. In addition, the capacity of AG-A to reduce cellular glutathione levels may contribute to the modulating activity of MRP1.
21286252 0020-7136 Journal Article