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Updated: Aug 3, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Early multidrug resistance, defined by changes in intracellular doxorubicin distribution, independent of

G J Schuurhuis1, H J Broxterman, J H de Lange

  • 1Department of Medical Oncology, Amsterdam, The Netherlands.

British Journal of Cancer
|November 1, 1991
PubMed

Insights

This study explores early steps in multidrug resistance in lung cancer cells. A P-glycoprotein-independent mechanism reduces doxorubicin accumulation, potentially preceding P-glycoprotein expression in cancer drug resistance.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) in cancer is often linked to P-glycoprotein (Pgp) efflux pumps.
  • However, Pgp overexpression doesn't explain resistance in all human cancers.
  • Early resistance mechanisms independent of Pgp warrant investigation.

Purpose of the Study:

  • To characterize early events in multidrug resistance development.
  • To investigate Pgp-independent mechanisms of anticancer drug resistance.
  • To analyze doxorubicin cellular accumulation in Pgp-positive and Pgp-negative resistant cell lines.

Main Methods:

  • Developed Pgp-positive (Pgp/+) and Pgp-negative (Pgp/-) multidrug resistant cell lines from SW-1573 human non-small cell lung cancer cells.
  • Used stepwise selection with increasing doxorubicin concentrations.
  • Quantified doxorubicin fluorescence in the nucleus (N) and cytoplasm (C) using laserscan microscopy and image analysis.

Main Results:

  • The nucleus/cytoplasm (N/C) fluorescence ratio of doxorubicin decreased in both Pgp/+ and Pgp/- cells with increasing resistance.
  • Parent cells showed an N/C ratio of 3.8, decreasing to 1.2-2.6 in resistant cells.
  • Verapamil partially restored N/C ratios only in Pgp/+ cells, suggesting a Pgp-independent effect in Pgp/- cells.

Conclusions:

  • A Pgp-independent mechanism contributes to reduced doxorubicin accumulation in resistant cancer cells.
  • This mechanism may represent an early defense strategy preceding Pgp expression.
  • N/C ratio measurement could identify general Pgp-independent anticancer drug resistance.

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