Abstract 1808: Enhancing the Stupp regimen in glioblastoma cancer cells with a T-type calcium channels inhibitor

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor. Although introduction of the Stupp regimen combining radiation (IR) with concomitant and adjuvant temozolomide (TMZ) led to increased patient survival, the cure rate of GBM is disappointing. We postulated that sensitization of cancer cells to therapy can be achieved by targeting intracellular pathways and processes. Recently, T-type Ca2+ channels have been proposed as a molecular target for GBM sensitization to chemo- and radiotherapy (Keir et al., 2013; Sheehan et al., 2013). In the present studies, we investigated the effects of T-type channel inhibition on GBM cells’ responses to the Stupp regimen. GBM cells differing in their resistance to TMZ and IR were treated with theT-type channel antagonist, mibefradil, either concomitantly with TMZ or sequentially (Interlaced TherapyTM). Cell viability and clonogenic survival were determined, demonstrating significant enhancement of the Stupp regimen's anticancer effects with co-treatment with T-type channels inhibitors. Importantly for DNA-targeted therapies, we observed a decrease in cells’ ability to repair DNA damage in the presence of mibefradil. The molecular mechanism of this decrease was investigated by assessing expression levels, localization and phosphorylation status of ATM, DNA-PK, γH2AX, Chk1/2, Kap1, p53, Rad51. These mechanistic studies demonstrated that inhibiting T-type Ca2+ channels in GBM affects DNA damage signaling and repair through reduction of repair protein activation and changes their cellular localization. The observed effects are specific for T-type channels inhibition, since L-type channels inhibitors had no effect. Our study provide a rational molecular mechanism for sensitization of GBM to the Stupp regimen by T-type Ca2+ channel inhibition, which will facilitate current and future clinical trials and potentially lead to new treatment options for this deadly brain tumor. Citation Format: Jaroslaw Dziegielewski, Barbara Dziegielewska, Lloyd S. Gray. Enhancing the Stupp regimen in glioblastoma cancer cells with a T-type calcium channels inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1808. doi:10.1158/1538-7445.AM2015-1808