title: T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin.
abstract: 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 calcium (Ca(2+)) channels play a reinforcing role in cancer cell proliferation, cell-cycle progression, and apoptosis evasion. Therefore, we investigated whether T-type Ca(2+) channels affect ovarian tumor growth and response to platinum agents. Inhibition of T-type Ca(2+) 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 antiapoptotic 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 the 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.
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dziegielewska
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Eli V
authors.initials: EV
authors.lastname: Casarez
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.
authors.forename: Wesley Z
authors.initials: WZ
authors.lastname: Yang
authors.affiliation: Cavion LLC, Charlottesville, Virginia.
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Gray
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia. Cancer Center, University of Virginia, Charlottesville, Virginia.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Dziegielewski
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia. Cancer Center, University of Virginia, Charlottesville, Virginia. jks6a@virginia.edu.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Slack-Davis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D020748:Mibefradil / Q000494:pharmacology; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D020748:Mibefradil; D016190:Carboplatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
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