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Clotrimazole inhibits cell proliferation in vitro and in vivo

Nature Medicine volume 1, pages 534–540 (1995)Cite this article

An Erratum to this article was published on 01 July 1995

Abstract

Cell proliferation is critically dependent on the regulated movement of ions across various cellular compartments. The antimycotic drug clotrimazole (CLT) has been shown to inhibit movement of Ca2+ and K+ across the plasma membrane. Our results show that CLT inhibits the rate of cell proliferation of normal and cancer cell lines in a reversible and dose-dependent manner in vitro. Moreover, CLT depletes the intracellular Ca2+ stores and prevents the rise in cytosolic Ca2+ that normally follows mitogenic stimulation. In mice with severe combined immunodeficiency disease (SCID) and inoculated intravenously with MM-RU human melanoma cells, daily subcutaneous injections of CLT induced a significant reduction in the number of lung metastases. Modulation of early ionic mitogenic signals and potent inhibition of cell proliferation both in vitro and in vivo are new and potentially useful clinical effects of CLT.

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References

  1. Rozengurt, E. Early signals in mitogenic response. Science 234, 161–164 (1986).

    Article  CAS  Google Scholar 

  2. Tsien, R.W. & Tsien, R.T. Calcium channels, stores, and oscillations. Annu. Rev. Cell Biol. 6, 715–760 (1990).

    Article  CAS  Google Scholar 

  3. Peppelenbosch, M.P., Tertoolen, L.G. & de Laat, S. W. Epidermal growth factor-activated calcium and potassium channels. J. biol. Chem. 266, 19938–19944 (1991).

    CAS  PubMed  Google Scholar 

  4. Magni, M., Meldolesi, J. & Pandiella, A. Ionic events induced by epidermal growth factor. J. biol. Chem. 261, 9321–9327 (1991).

    Google Scholar 

  5. Villalobos, C., Fonteriz, R., Lopez, M., Garcia, A.G. & Garcia-Sancho, J. Inhibition of voltage-gated Ca++ entry into GH3 and chromaffin cells by imidazole antimycotics and other cytochrome P450 blockers. FASEB J. 6, 2742–2747 (1992).

    Article  CAS  Google Scholar 

  6. Montero, M., Alvarez, J. & Garcia-Sancho, J. Agonist-induced Ca++ influx in human neutrophils is secondary to the emptying of intracellular calcium stores. Biochem. J. 277, 73–79 (1991).

    Article  CAS  Google Scholar 

  7. Alvarez, J., Montero, M. & Garcia-Sancho, J. High affinity inhibition of the Ca++-dependent K+ channels by cytochrome P-450 inhibitors. J. biol. Chem. 267, 11789–11793 (1992).

    CAS  PubMed  Google Scholar 

  8. Byers, H.R. et al. Cell migration and actin organization in cultured human primary recurrent cutaneous and metastatic melanoma. Am. J. Pathol. 139, 423–435 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsien, R.Y., Pozzan, T. & Rink, T.J. T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature 295, 68–70 (1982).

    Article  CAS  Google Scholar 

  10. Lytton, J., Westlin, M. & Hanley, M.R. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca++-ATPase family of calcium pumps. J. biol. Chem. 66, 17067–17071 (1991).

    Google Scholar 

  11. Putney, J.W. Jr. Receptor-regulated calcium entry. Pharmac. Ther. 48, 427–434 (1990).

    Article  CAS  Google Scholar 

  12. Montero, M., Garcia-Sancho, J. & Alvarez, J. Comparative effects of cytochrome P-450 inhibitors on Ca2+ and Mn2+ entry induced by agonists or by emptying the Ca2+ stores of human neutrophils. Biochem. biophys. Acta 1177, 127–133 (1993).

    Article  CAS  Google Scholar 

  13. Vostal, J.G. & Fratantoni, J.C. Econazole inhibits thapsigargin-induced calcium influx by mechanisms other than cytochrome P-450 inhibition. Biochem. J. 295, 525–529 (1993).

    Article  CAS  Google Scholar 

  14. Short, A.D. et al. Intracellular Ca++ pool content is linked to control of Cell growth. Proc. natn. Acad. Sci. U.S.A. 90, 4986–4990 (1993).

    Article  CAS  Google Scholar 

  15. Byers, H.R., Etoh, T., Lee, K.W., Mihm, S. & Gattoni-Celli, S. Organ specific metastasis in immunodeficient mice injected with human melanoma cells: A quantitative pathologic analysis. Melanoma Res. 3, 247–253 (1993).

    Article  CAS  Google Scholar 

  16. Randriamampita, C. & Tsien, R.Y. Emptying of intracellular Ca++ stores releases a novel small messenger that stimulates Ca++ influx. Nature 364, 809–813 (1993).

    Article  CAS  Google Scholar 

  17. Clapham, D.E. Cellular calcium. A mysterious new influx factor? Nature 364, 763–764 (1993).

    Article  CAS  Google Scholar 

  18. Putney, J.W. Jr. Excitement about calcium signaling in inexcitable cells. Science 262, 676–678 (1993).

    Article  Google Scholar 

  19. Sheets, J.J., Mason, J.I., Wise, C.A. & Estabrook, R.W. Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents. Biochem. Pharmac. 35, 487–491 (1986).

    Article  CAS  Google Scholar 

  20. Miles, S.A. et al. Oncostatin M as a potent mitogen for AIDS-Kaposi's sarcoma-derived cells. Science 255, 1432–1434 (1992).

    Article  CAS  Google Scholar 

  21. Logan, D.M. et al. Differences in the identification of both autocrine and paracrine growth factors capable of enhancing epidemic Kaposi's sarcoma (EKS)-derived cell culture proliferation in vitro . Int. Conf. AIDS 9, 399 (1993).

    Google Scholar 

  22. Cuttitta, F. et al. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature 316, 823–826 (1985).

    Article  CAS  Google Scholar 

  23. Benzaquen, L., Nicholson Weller, A. & Halperin, J.A. Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J. exp. Med. 179, 985–992 (1993).

    Article  Google Scholar 

  24. French, J.E. Atherosclerosis in relation to the structure and function of the arterial intima, with special reference to the endothelium. Int. Rev. exp. Pathol. 5, 253–353 (1966).

    CAS  PubMed  Google Scholar 

  25. Floege, J. et al. Rat glomerular mesangial cells synthesize basic fibroblast growth factor. Release, upregulated synthesis, and mitogenicity in mesangial proliferative glomerulonephritis. J. clin. Invest. 90, 2362–2369 (1993).

    Article  Google Scholar 

  26. Eguchi, K. et al. Fibroblast growth factors released by wounded endothelial cells stimulate proliferation of synovial cells. J. Rheumat. 19, 1925–1932 (1992).

    CAS  Google Scholar 

  27. Ross, R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 362, 801–809 (1993).

    Article  CAS  Google Scholar 

  28. Seo, M., Iida, H. & Miura, Y. Basic experiments with clotrimazole administered orally. Curr. med. Res. Opin. 5, 169–178 (1977).

    Article  CAS  Google Scholar 

  29. Weuta, H. Clinical studies with oral clotrimazole. Postgrad. Med. J. (July suppl.) 50, 45–49 (1974).

    Article  Google Scholar 

  30. Halperin, J.A., Taratuska, A. & Nicholson-Weller, A. Complement protein C5b-9 stimulates mitogenesis in 3T3 cells. J. clin. Invest. 91, 1974–1978 (1993).

    Article  CAS  Google Scholar 

  31. Borzak, S. et al. In situ calibration of Fura-2 and BCECF fluorescence in adult ventricular myocytes. Am. J. Physiol. 259, H973–H981 (1990).

    CAS  PubMed  Google Scholar 

  32. Berger, H.J., Taratuska, A., Smith, T.W. & Halperin, J. Activated complement directly modifies the performance of isolated heart muscle cells from guinea pig and rat. Am. J. Physiol. 265, H267–H272 (1993).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts, 02115, USA

    Laura R. Benzaquen

  2. Hematology Laboratory, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Carlo Brugnara

  3. Department of Dermatology, Boston University School of Medicine, 80 East Concord Street, Boston, Massachusetts, 02118, USA

    H. Randolph Byers

  4. Department of Radiation Oncology, Medical University of South Carolina, 171 Ashley Avenue, Room 168, Charleston, South Carolina, 29425, USA

    Sebastiano Gattoni-Celli

  5. Department of Cell Biology, Harvard Medical School, 25 Shattuck Street, Building C1-607, Boston, Massachusetts, 02115, USA

    José A. Halperin

Authors
  1. Laura R. Benzaquen
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  2. Carlo Brugnara
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  3. H. Randolph Byers
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  4. Sebastiano Gattoni-Celli
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  5. José A. Halperin
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Benzaquen, L., Brugnara, C., Byers, H. et al. Clotrimazole inhibits cell proliferation in vitro and in vivo. Nat Med 1, 534–540 (1995). https://doi.org/10.1038/nm0695-534

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