T-type calcium channels as a therapeutic target for intracranial tumors?aDepartment of Neurological Surgery Loyola University Medical Center, Maywood, Illinois United States
Aim: Our previous studies have shown that calcium ions (Ca2+) provide important proliferative signals for cultured intracranial tumor cells. L-type Ca2+ channel blockers inhibited proliferation of these cells as well as growth of xenografted tumors in athymic rats. Because the involvement of transient intracellular Ca2+ signaling is important in cell cycle progression, the aim of this study is to test if T-type Ca2+ channels may also play an important role in proliferation. Methods: 1) Dose-response effects of the T-type calcium blocking agent Mibefradil on proliferation of cultured human astrocytoma (U87-MG) and neuroblastoma (N1E-115) cell were compared to L-type blockers nifedipine and verapamil. 2) Proliferative effects of overexpression of T-type channel protein using an adenovirus vector containing mRNA for the alpha 1H subunit of the T-type Ca2+ channel as well as the effects of antisense oligonucleotide against mRNA for alpha 1G subunit were studied. Transfection efficiency was determined by counting FITC labeled cells using fluorescence microscopy. Nonsense and scrambled nucleotides were used as controls. Proliferation rates in all groups were studied for up to seven days. Results: Mibefradil inhibited tumor cell proliferation with an EC50 which was about 1/30 of that of L-channel blockers. Overexpression of T-type channel protein, doubled the proliferation rate , and antisense reduced the proliferation rate to 45% at day 4. In Cos-7 tumor cells not expressing T-type channels, the antisense had no proliferative effect. Conclusion: These studies support the concept that these channels play a role in proliferation of some intracranial tumors, suggesting possible therapeutic considerations.
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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prevention.