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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Reversal effects of antifungal drugs on multidrug resistance in MDR1-overexpressing HeLa cells

N Iida1, K Takara, N Ohmoto

  • 1Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.

Biological & Pharmaceutical Bulletin
|September 18, 2001
PubMed

Insights

Multidrug resistance in HeLa cervical cancer cells was studied. Itraconazole effectively reversed resistance to vinblastine and paclitaxel by inhibiting drug accumulation, showing potential for combination cancer therapy.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, limiting the efficacy of various anticancer drugs.
  • The human cervical carcinoma cell line HeLa-Ohio (HeLa) and a derived multidrug-resistant cell line (Hvr100-6) were utilized to investigate resistance mechanisms and potential reversal agents.

Purpose of the Study:

  • To characterize the drug resistance profile of Hvr100-6 cells, which were developed by exposing HeLa cells to increasing concentrations of vinblastine.
  • To evaluate the potential of several antifungal drugs, including itraconazole, to reverse acquired multidrug resistance in cancer cells.
  • To elucidate the mechanism by which itraconazole reverses multidrug resistance.

Main Methods:

  • Antiproliferative effects of vinblastine, paclitaxel, doxorubicin, daunorubicin, and 5-fluorouracil were assessed in HeLa and Hvr100-6 cells.
  • Flow cytometry was used to analyze the expression of MDR1 (P-glycoprotein) and MRP.
  • The reversal effects of antifungal agents on drug resistance were evaluated, and drug accumulation was measured.

Main Results:

  • Hvr100-6 cells exhibited significant resistance to vinblastine, paclitaxel, doxorubicin, and daunorubicin, but not to 5-fluorouracil.
  • MDR1 (P-glycoprotein) expression was induced in Hvr100-6 cells, while MRP levels remained unchanged.
  • Itraconazole demonstrated a potent, dose-dependent reversal of resistance to vinblastine and paclitaxel by inhibiting the accumulation of these anticancer drugs.

Conclusions:

  • Acquired resistance in Hvr100-6 cells is associated with MDR1 induction and affects multiple anticancer drugs.
  • Itraconazole is a promising agent for overcoming vinblastine and paclitaxel resistance in cervical cancer.
  • The mechanism of itraconazole's reversal effect involves the inhibition of intracellular anticancer drug accumulation.

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