Abstract A239: T-type calcium channels as a novel molecular target for tumor therapy.

Abstract

T-type Ca2+ channels are a group of low voltage-gated calcium channels which seem to be crucial for embryonic or stem cell proliferation and differentiation; however, they could be also aberrantly expressed in several human tumors. Since calcium entry is required for smooth transition through the cell cycle, it has been hypothesized that the inhibition of T-type Ca2+ channels blocks cells in G0/G1 phase of cell cycle, while a release from inhibition leads to increased number of cells entering cell cycle and thus increased susceptibility to conventional antitumor therapy. In this study we investigated the effects of T-type channel inactivation, or downregulation, on cell cycle progression, cell death and survival, and resistance to radiotherapy (RT). The experiments were conducted using several cancer cell lines expressing T-type Ca2+ channels (glioblastoma, colon and prostate) and selective and structurally unrelated calcium channels antagonists, including Mibefradil, a drug that is currently undergoing clinical trial for its antitumor properties, and is planned to be tested as radiosensitizing agent in recurrent gliobastoma tumors. The effects of T-type Ca2+ channel inhibition on cell cycle progression, cell death and the expression/activation of cell cycle regulated proteins were assessed. Finally, the combination treatments including T-type channel antagonist and radiotherapy were assayed. We show that T-type Ca2+ channels are important for cell cycle progression and resistance to RT, and that their inhibition leads to enhanced cell death and reduced survival. Our study demonstrates that one of the earliest events evoked by T-type channel inhibition is a deregulation of pro-survival pathway PI3K/Akt/mTOR and activation of pro-apoptotic stress-activated p38MAPK pathway. The results support the idea of T-type Ca2+ channel as a novel molecular target for antitumor therapy and provide a rational and plausible biological mechanism responsible for the effects induced by T-type Ca2+ channel antagonists in cancer cells. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A239. Citation Format: Barbara Dziegielewska, Nicholas C.K. Valerie, Amol S. Hosing, James M. Larner, David L. Brautigan, Lloyd S. Gray, Jaroslaw Dziegielewski. T-type calcium channels as a novel molecular target for tumor therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A239.