MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bertolesi, G. E.
Right arrow Articles by Kelly, M. E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bertolesi, G. E.
Right arrow Articles by Kelly, M. E. M.

Vol. 62, Issue 2, 210-219, August 2002

The Ca2+ Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms

Gabriel E. Bertolesi, Chanjuan Shi, Lindsy Elbaum, Christine Jollimore, Gabriela Rozenberg, Steven Barnes, and Melanie E. M. Kelly

Laboratory of Retina and Optic Nerve Research, Departments of Ophthalmology (G.E.B., C.S., C.J., S.B., M.E.M.K.), Pharmacology (G.E.B., C.S., L.E., C.J., M.E.M.K.), and Physiology & Biophysics (G.E.B., G.R., S.B.), Dalhousie University, Halifax, Nova Scotia, Canada

We show that mitogenic cells expressing T-type Ca2+ channels (T-channels) are more sensitive to the antiproliferative effects of the drugs pimozide and mibefradil than cells without significant T-channel expression. The growth of Y79 and WERI-Rb1 retinoblastoma cells, as well as MCF7 breast cancer epithelial cells, all of which express T-channel current and mRNA for T-channel subunits, is inhibited by pimozide and mibefradil with IC50 values between 0.6 and 1.5 µM. Proliferation of glioma C6 cells, which show little T-channel expression, is less sensitive to these drugs (IC50 = 8 and 5 µM for pimozide and mibefradil, respectively). Neither drug seems to alter cell cycle or the expression of cyclins. Although this strong correlation between T-channel expression and growth inhibition exists, the following results suggest that the drugs inhibit cell growth via different cytotoxic pathways: 1) pimozide and mibefradil have additive effects on T-channel current inhibition, whereas the antiproliferative activity of the drugs together is synergistic; 2) an increase in the number of apoptotic Y79 and MCF7 cells and a decrease in the mRNA for the antiapoptotic gene Bcl-2 is detected only in pimozide-treated cells, whereas in mibefradil-treated cells, the toxicity is primarily necrotic; and 3) growth inhibition by mibefradil is reduced in Y79 cells transfected with T-channel antisense and in differentiated Y79 cells (which have decreased T-channel expression), but growth inhibition by pimozide is affected to a lesser extent. These results suggest that pimozide and mibefradil inhibit cell proliferation via different cytotoxic pathways and that in the case of pimozide, it is unlikely that this effect is mediated solely by T-channel inhibition.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Am. J. Physiol. Renal Physiol.Home page
M.-G. Feng and L. G. Navar
Nitric oxide synthase inhibition activates L- and T-type Ca2+ channels in afferent and efferent arterioles
Am J Physiol Renal Physiol, April 1, 2006; 290(4): F873 - F879.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
D. M. Rodman, K. Reese, J. Harral, B. Fouty, S. Wu, J. West, M. Hoedt-Miller, Y. Tada, K.-X. Li, C. Cool, et al.
Low-Voltage-Activated (T-Type) Calcium Channels Control Proliferation of Human Pulmonary Artery Myocytes
Circ. Res., April 29, 2005; 96(8): 864 - 872.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
D. C. Baptiste, A. T. E. Hartwick, C. A. B. Jollimore, W. H. Baldridge, G. M. Seigel, and M. E. M. Kelly
An Investigation of the Neuroprotective Effects of Tetracycline Derivatives in Experimental Models of Retinal Cell Death
Mol. Pharmacol., November 1, 2004; 66(5): 1113 - 1122.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. Cataldi, A. Gaudino, V. Lariccia, M. Russo, S. Amoroso, G. di Renzo, and L. Annunziato
Imatinib-Mesylate Blocks Recombinant T-Type Calcium Channels Expressed in Human Embryonic Kidney-293 Cells by a Protein Tyrosine Kinase-Independent Mechanism
J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 208 - 215.
[Abstract] [Full Text]

Home page
 BloodHome page
M. Yoshida, K. Nosaka, J.-i. Yasunaga, I. Nishikata, K. Morishita, and M. Matsuoka
Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells
Blood, April 1, 2004; 103(7): 2753 - 2760.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
M.-G. Feng, M. Li, and L. G. Navar
T-type calcium channels in the regulation of afferent and efferent arterioles in rats
Am J Physiol Renal Physiol, February 1, 2004; 286(2): F331 - F337.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
L. Ferron, V. Capuano, Y. Ruchon, E. Deroubaix, A. Coulombe, and J.-F. Renaud
Angiotensin II Signaling Pathways Mediate Expression of Cardiac T-Type Calcium Channels
Circ. Res., December 12, 2003; 93(12): 1241 - 1248.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics