T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin.
T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin.
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DOI：
10.1158/1535-7163.mct-15-0456
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发表时间：
2016-03
影响因子：
5.7
通讯作者：
Slack-Davis JK
中科院分区：
文献类型：
--
作者：
Dziegielewska B;Casarez EV;Yang WZ;Gray LS;Dziegielewski J;Slack-Davis JK
Ovarian cancer is the deadliest gynecologic cancer, due in large part to the diagnosis of advanced stage disease, the development of platinum resistance, and inadequate treatment alternatives. Recent studies by our group and others have shown that T-type Ca2+ channels play a reinforcing role in cancer cell proliferation, cell cycle progression and apoptosis evasion. Therefore, we investigated whether T-type Ca2+ channels affect ovarian tumor growth and response to platinum agents. Inhibition of T-type Ca2+ channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer cells with a simultaneous increase in apoptosis, which was accompanied by decreased expression of the anti-apoptotic gene survivin (BIRC5). Analysis of intracellular signaling revealed mibefradil reduced AKT phosphorylation, increased the levels and nuclear retention of FOXO transcription factors that repress BIRC5 expression, and decreased expression of FoxM1, which promotes BIRC5 expression. Combining carboplatin with mibefradil synergistically increased apoptosis in vitro. Importantly, mibefradil rendered platinum-resistant ovarian tumors sensitive to carboplatin in a mouse model of peritoneal metastasis. Together, the data provide rationale for future use of T-type channel antagonists together with platinum agents for the treatment of ovarian cancer.
