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


CONCLUSIONS
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.
Duffy
S Mark
SM
Division of Respiratory Medicine, Institute for Lung Health, University of Leicester Medical School, Leicester, United Kingdom.
Lawley
Wendy J
WJ
Kaur
Davinder
D
Yang
Weidong
W
Bradding
Peter
P
D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004553:Electric Conductivity; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D007938:Leukemia / Q000473:pathology; D008168:Lung / Q000166:cytology; D008407:Mast Cells / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
D007473:Ion Channels; D013629:Tamoxifen; D006632:Histamine; D019009:Proto-Oncogene Proteins c-kit; D002118:Calcium