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The antiproliferative properties of tamoxifen and phenothiazines may be mediated by a unique histamine receptor (?H3) distinct from the calmodulin-binding site

  • Original Articles
  • Tamoxifen, Phenothiazines, Calmodulin
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Summary

N,N-diethyl-2-[(4-phenylmethyl)-phenoxyl]-ethanamine HCl (DPPE), a novel histamine antagonist (?H3), which selectively binds with high affinity to the antiestrogen-binding site (AEBS/?H3), inhibits the activity of calmodulin-dependent myosin light chain kinase (MLCK) only at concentrations >1 mM, as opposed to tamoxifen (TAM), which has an IC50=4 μM in the same assay. This suggests that the antiestrogen-binding site is distinct from the site on calmodulin which binds TAM and phenothiazines. However, at an in vitro concentration of 1×10-6 M, the antiproliferative effects of DPPE and several phenothiazines, which also compete for binding to AEBS/?H3, are about equal; this suggests that affinity for AEBS/?H3 rather than that for the calmodulin-binding site may correlate with clinically relevant antigrowth effects of these compounds.

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Authors and Affiliations

  1. Department of Medicine, University of Manitoba, 100 Olivia Street, R3E 0V9, Winnipeg, Manitoba, Canada

    Lorne J. Brandes

  2. Department of Pharmacology, University of Manitoba, 100 Olivia Street, R3E 0V9, Winnipeg, Manitoba, Canada

    Lorne J. Brandes & Ratna Bose

  3. The Manitoba Institute of Cell Biology, University of Manitoba, 100 Olivia Street, R3E 0V9, Winnipeg, Manitoba, Canada

    Lorne J. Brandes, R. Patricia Bogdanovic & Max D. Cawker

Authors
  1. Lorne J. Brandes
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  2. R. Patricia Bogdanovic
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  3. Max D. Cawker
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  4. Ratna Bose
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Additional information

This work was supported by grants from the National Cancer Institute of Canada, the Medical Research Council of Canada, and by a generous gift from the estate of Alice Christle.

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Brandes, L.J., Bogdanovic, R.P., Cawker, M.D. et al. The antiproliferative properties of tamoxifen and phenothiazines may be mediated by a unique histamine receptor (?H3) distinct from the calmodulin-binding site. Cancer Chemother. Pharmacol. 18, 21–23 (1986). https://doi.org/10.1007/BF00253057

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  • DOI: https://doi.org/10.1007/BF00253057

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