COMPETITIVE-INHIBITION BY GENISTEIN AND ATP DEPENDENCE OF DAUNORUBICIN TRANSPORT IN INTACT MRP OVEREXPRESSING HUMAN SMALL-CELL LUNG-CANCER CELLS

被引：108

作者：

VERSANTVOORT, CHM ^{[1
]}

BROXTERMAN, HJ ^{[1
]}

LANKELMA, J ^{[1
]}

FELLER, N ^{[1
]}

PINEDO, HM ^{[1
]}

机构：

[1] FREE UNIV AMSTERDAM HOSP,DEPT MED ONCOL,1081 HV AMSTERDAM,NETHERLANDS

来源：

BIOCHEMICAL PHARMACOLOGY | 1994年 / 48卷 / 06期

关键词：

MULTIDRUG RESISTANCE; CELLULAR DAUNORUBICIN ACCUMULATION; ATP; GENISTEIN; MRP; (NON) P-GLYCOPROTEIN;

D O I：

10.1016/0006-2952(94)90149-X

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

In several multidrug resistant tumor cell lines without overexpression of P-glycoprotein (non-Pgp MDR), a decreased accumulation of drugs has been shown to contribute to resistance. We have recently reported that daunorubicin (DNR) accumulation was decreased in the multidrug resistance-associated protein overexpressing GLC4/ADR non-Pgp MDR small cell lung cancer cell line due to an enhanced energy-dependent efflux which could be inhibited by the isoflavonoid genistein. The purpose of this work was 2-fold: (i) to investigate the mechanism by which genistein inhibits the DNR efflux in the GLC4/ADR cells; and (ii) to characterize the dependence of DNR transport on ATP concentration in intact GLC4/ADR cells. The active transport of DNR in GLC4/ADR cells appeared to be a saturable process with an apparent K-m of DNR of 1.4 +/- 0.4 mu M. Genistein increased the apparent K-m value of DNR, suggesting that this agent is a competitive inhibitor of DNR transport. These data provide additional evidence that energy-dependent DNR transport in GLC4/ADR cells is a protein-mediated process. In addition, genistein decreased cellular ATP concentration in a dose-dependent manner in sensitive as well as in resistant cells. Marked inhibition of DNR transport activity in intact GLC4/ADR cells was found when cellular ATP concentration was decreased below 2 mM by sodium azide or 2-deoxy-D-glucose. Thus, since DNR transport in intact GLC4/ADR is already inhibited at modest cellular ATP depletion, a limitation in ATP supply might open ways to make MDR cells more susceptible to drug toxicity.

引用

页码：1129 / 1136

页数：8

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