Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small cell lung cancer cells

Carolien H M Versantvoort, Henk J. Broxterman, Jan Lankelma, Nicole feller, Herbert M. Pinedo

Research output: Contribution to journalArticlepeer-review

Abstract

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 Km of DNR of 1.4 ± 0.4μM. Genistein increased the apparent Km 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.

Original languageEnglish (US)
Pages (from-to)1129-1136
Number of pages8
JournalBiochemical Pharmacology
Volume48
Issue number6
DOIs
StatePublished - Sep 15 1994
Externally publishedYes

Keywords

  • (non) P-glycoprotein
  • ATP
  • genistein
  • MRP
  • multidrug resistance: cellular daunorubicin accumulation

ASJC Scopus subject areas

  • Pharmacology

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