Inhibition of human mast cell proliferation and survival by tamoxifen in association with ion channel modulation

J Allergy Clin Immunol. 2003 Nov;112(5):965-72. doi: 10.1016/j.jaci.2003.07.004.

Abstract

Background: Human lung mast cells (HLMCs) and the human mast cell line HMC-1 express a strongly outwardly rectifying Cl- current characteristic of that carried by the voltage-dependent Cl- channel ClC-5. A similar but distinct current has been implicated in the control of cell proliferation in astrocytes.

Objective: In this study, we have examined the effects of the Cl- channel blocker tamoxifen on ion channel activity and cell proliferation in both HMC-1 and HLMCs.

Methods: We used the whole-cell patch-clamp technique to characterize macroscopic ion currents in mast cells before and after addition of tamoxifen. HMC-1 proliferation was assessed by incorporation of tritiated thymidine, HLMC proliferation was determined by counting cells in long-term culture, and cell viability was assessed by annexin V binding and propidium iodide uptake.

Results: In HMC-1, tamoxifen reduced the outward Cl- current at +130 mV by 73% +/- 9% at a concentration of 3 micromol/L and simultaneously opened a novel inwardly rectifying nonselective cation current with a mean inward current of 153 +/- 18 pA at -130 mV. Tamoxifen produced a dose-dependent inhibition of HMC-1 proliferation (90.3% +/- 4.0% inhibition at 30 micromol/L) without altering cell viability. Tamoxifen inhibited the outward ClC-5-like current in HLMCs, did not open an inward current, and produced a dose-dependent inhibition of HLMC proliferation in long-term culture.

Conclusion: Tamoxifen inhibits HMC proliferation, possibly through ion channel modulation. This suggests that tamoxifen might be useful in the treatment of mast-cell-mediated diseases, including mastocytosis, asthma, and pulmonary fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Cell Division / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Electric Conductivity
  • Histamine / metabolism
  • Humans
  • Ion Channels / metabolism*
  • Leukemia / pathology
  • Lung / cytology
  • Mast Cells / cytology
  • Mast Cells / pathology*
  • Mast Cells / physiology*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-kit / metabolism
  • Tamoxifen / pharmacology*

Substances

  • Ion Channels
  • Tamoxifen
  • Histamine
  • Proto-Oncogene Proteins c-kit
  • Calcium