The 2-phenylaminopyrimidine derivative imatinib-mesylate, a powerful protein tyrosine kinase (PTK) inhibitor that targets abl, c-kit, and the platelet-derived growth factor receptors, is rapidly gaining a relevant role in the treatment of several types of neoplasms. Because first generation PTK inhibitors affect the activity of a large number of voltage-dependent ion channels, the present study explored the possibility that imatinib-mesylate could interfere with the activity of T-type channels, a class of voltage-dependent Ca2+ channels that take part in the chain of events elicited by PTK activation. The effect of the drug on T-type channel activity was examined using the whole-cell patch-clamp technique with Ba2+ (10 mM) as the permeant ion in human embryonic kidney-293 cells, stably expressing the rat CaV3.3 channels. Imatinib-mesylate concentrations, ranging from 30 to 300 µM, reversibly decreased CaV3.3 current amplitude with an IC50 value of 56.9 µM. By contrast, when imatinib-mesylate (500 µM) was intracellularly dialyzed with the pipette solution, no reduction in Ba2+ current density was observed. The 2-phenylaminopyrimidine derivative modified neither the voltage dependence of activation nor the steady-state inactivation of CaV3.3 channels. The decrease in extracellular Ba2+ concentration from 10 to 2 mM and the substitution of Ca2+ for Ba2+ increased the extent of 30 µM imatinib-mesylate-induced percentage of channel blockade from 25.9 ± 2.4 to 36.3 ± 0.9% in 2 mM Ba2+ and 44.2 ± 2.3% in 2 mM Ca2+. In conclusion, imatinib-mesylate blocked the cloned CaV3.3 channels by a PTK-independent mechanism. Specifically, the drug did not affect the activation or the inactivation of the channel but interfered with the ion permeation process.

IMATINIB-MESYLATE BLOCKS RECOMBINANT T-TYPE CALCIUM CHANNELS EXPRESSED IN HEK-293 CELLS BY A PTK-INDEPENDENT MECHANISM

CATALDI, MAURO;LARICCIA, Vincenzo;RUSSO, MICHELA;DI RENZO, GIANFRANCO MARIA LUIGI;ANNUNZIATO, LUCIO
2004

Abstract

The 2-phenylaminopyrimidine derivative imatinib-mesylate, a powerful protein tyrosine kinase (PTK) inhibitor that targets abl, c-kit, and the platelet-derived growth factor receptors, is rapidly gaining a relevant role in the treatment of several types of neoplasms. Because first generation PTK inhibitors affect the activity of a large number of voltage-dependent ion channels, the present study explored the possibility that imatinib-mesylate could interfere with the activity of T-type channels, a class of voltage-dependent Ca2+ channels that take part in the chain of events elicited by PTK activation. The effect of the drug on T-type channel activity was examined using the whole-cell patch-clamp technique with Ba2+ (10 mM) as the permeant ion in human embryonic kidney-293 cells, stably expressing the rat CaV3.3 channels. Imatinib-mesylate concentrations, ranging from 30 to 300 µM, reversibly decreased CaV3.3 current amplitude with an IC50 value of 56.9 µM. By contrast, when imatinib-mesylate (500 µM) was intracellularly dialyzed with the pipette solution, no reduction in Ba2+ current density was observed. The 2-phenylaminopyrimidine derivative modified neither the voltage dependence of activation nor the steady-state inactivation of CaV3.3 channels. The decrease in extracellular Ba2+ concentration from 10 to 2 mM and the substitution of Ca2+ for Ba2+ increased the extent of 30 µM imatinib-mesylate-induced percentage of channel blockade from 25.9 ± 2.4 to 36.3 ± 0.9% in 2 mM Ba2+ and 44.2 ± 2.3% in 2 mM Ca2+. In conclusion, imatinib-mesylate blocked the cloned CaV3.3 channels by a PTK-independent mechanism. Specifically, the drug did not affect the activation or the inactivation of the channel but interfered with the ion permeation process.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/204038
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