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Daunorubicin efflux against a concentration gradient in non-P-glycoprotein multidrug-resistant lung-cancer cells

H S Mülder1, J Lankelma, H Dekker

  • 1Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.

International Journal of Cancer
|October 15, 1994
PubMed

Insights

Multidrug-resistant lung cancer cells lacking P-glycoprotein show active daunorubicin efflux via a novel pump. Vincristine inhibits this efflux, suggesting a new multidrug transporter involved in drug resistance.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Oncology

Background:

  • Multidrug resistance (MDR) in cancer is a major therapeutic challenge.
  • Human non-small-cell lung carcinoma SW-1573/2R120 cells exhibit MDR independent of P-glycoprotein (Pgp).
  • These cells show reduced daunorubicin (DN) accumulation, suggesting an active efflux mechanism.

Purpose of the Study:

  • To provide further evidence for an active drug efflux pump in non-Pgp MDR cells.
  • To estimate the active drug pump flux.
  • To characterize the interaction of vincristine (VCR) with this efflux system.

Main Methods:

  • Exposure of cells to daunorubicin (DN) in a flowing medium to reach steady state.
  • Pulsatile injection of vincristine (VCR) to assess its effect on cellular DN content.
  • Varying extracellular DN and VCR concentrations to study competitive interactions and pump kinetics.

Main Results:

  • Vincristine (VCR) rapidly increased cellular daunorubicin (DN) content in non-Pgp MDR cells, indicating efflux pump inhibition.
  • Accumulated DN was effluxed against a concentration gradient after VCR pulse removal.
  • VCR-induced DN influx showed saturation kinetics and competitive interaction with DN, suggesting a shared transporter.
  • Similar effects were observed in Pgp-expressing and other non-Pgp MDR cell lines.

Conclusions:

  • Evidence supports an active DN efflux system in non-Pgp MDR cells, distinct from P-glycoprotein.
  • This system functions as a multidrug transporter, mediating efflux against a concentration gradient.
  • Vincristine acts as an inhibitor of this putative transporter, offering potential therapeutic insights.

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