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The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms

Gabriel E Bertolesi1, Chanjuan Shi, Lindsy Elbaum

  • 1Laboratory of Retina and Optic Nerve Research, Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada.

Molecular Pharmacology
|July 20, 2002
PubMed

Insights

Cancer cells with T-type calcium channels (T-channels) are more sensitive to pimozide and mibefradil. These drugs inhibit cell growth through distinct cytotoxic pathways, suggesting complex mechanisms beyond T-channel blockade.

Area of Science:

  • Cell Biology
  • Pharmacology
  • Cancer Research

Background:

  • T-type calcium channels (T-channels) are implicated in cell proliferation.
  • Antiproliferative drugs like pimozide and mibefradil are used in cancer treatment.
  • Understanding drug mechanisms and cellular targets is crucial for effective cancer therapy.

Purpose of the Study:

  • To investigate the correlation between T-channel expression and sensitivity to pimozide and mibefradil.
  • To elucidate the distinct cytotoxic pathways employed by these drugs.
  • To determine if T-channel inhibition solely mediates the antiproliferative effects.

Main Methods:

  • Assessing drug sensitivity (IC50 values) in cell lines with varying T-channel expression.
  • Analyzing cell cycle progression and cyclin expression.
  • Evaluating drug effects on T-channel current, apoptosis, necrosis, and gene expression (Bcl-2).
  • Utilizing antisense and cell differentiation models to assess drug-specific effects.

Main Results:

  • Cells expressing T-channels showed higher sensitivity to pimozide and mibefradil (IC50 0.6-1.5 µM) compared to T-channel-low cells (IC50 5-8 µM).
  • Pimozide and mibefradil exhibited synergistic antiproliferative effects but additive T-channel current inhibition.
  • Pimozide induced apoptosis and decreased Bcl-2 mRNA, while mibefradil caused primarily necrotic cell death.
  • Growth inhibition by mibefradil was more dependent on T-channel expression than pimozide.

Conclusions:

  • Pimozide and mibefradil inhibit cancer cell proliferation via distinct cytotoxic mechanisms.
  • While T-channel expression correlates with sensitivity, pimozide's antiproliferative effect is unlikely mediated solely by T-channel inhibition.
  • These findings highlight the complex pharmacology of these agents and suggest potential for combination therapies targeting different pathways.

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