The purpose of this study is to develop a novel and effective mechanistic target for sensitizing glioblastoma tumors to anti-cancer therapy. Glioblastoma multiforme (GBM) are primary brain tumors with an exceptional resistance to radio- and chemotherapy and, therefore, have extremely poor prognosis. Conventional treatment consists of aggressive surgery, chemotherapy and/or radiotherapy; however in spite of these treatments, the median survival of GBM patients is only 9 to 12 months. T-type channels are a type of voltage-gated calcium channel important for normal cell proliferation and differentiation, but they could be also over-expressed or aberrantly activated in several human cancers, including GBM. In this study we investigate the effects of T-type channel inactivation, either by selective antagonists (mibefradil and TTL1177) or by siRNA-directed knock-down, on GBM cells survival and resistance to therapy in vitro. Our results show that blocking T-type channels not only reversibly arrests cells in G1/G0 phase of the cell cycle but also induces irreversible loss of clonogenic potential and cell death. The execution of cell death is preceded (or coincides) by induction of autophagy, as characterized by LC-3 cleavage and punctuate staining. Furthermore, we also establish that inactivation of T-type channels stimulates the extrinsic pathway of programmed cell death, as evidenced by caspase 8 activation and Bid protein cleavage. Finally, we demonstrate that inactivation of T-type calcium channels sensitizes GBM cells to radio- and chemotherapy. Taken together with the promising outcomes of the in vivo mibefradil plus temozolomide trials, our studies suggest that targeting T-type calcium channels could be a novel and very efficient therapy for glioblastoma brain tumors, either as a single modality or in combination with already established modalities. (This work was financed in part by the University of Virginia Cancer Center Pilot Grant, the Department of Radiation Oncology Pilot Grant and the Department of Chemistry Research Fund)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-262. doi:1538-7445.AM2012-LB-262

©2012 American Association for Cancer Research
2012