Inhibition of T-type Calcium Channels Suppresses Cell Proliferation and Invasion of Medulloblastoma Cells via Alterations in Cell Metabolic Activities [Poster]

Medulloblastoma (MB) is the most common malignant childhood brain cancer. The low efficacy and long-lasting side effects of current therapies necessitate the need for a new treatment for MB. In this study, in-silico transcriptomics analysis of MB patients revealed a significant correlation of a CaV3 calcium channel expression with metastasis and patient survival rates. Pharmacological inhibition of CaV3 (T-type) calcium channels by mibefradil or NNC-55-0396 (NNC) significantly reduced MB cell proliferation and resistance to an MB chemotherapeutic agent, vincristine, as assessed by WST-1 proliferation assay. Mibefradil or NNC treatment further reduced the invasive abilities of MB cells in an agar invasion assay. These responses were specific to T-type calcium channel blockade as inhibition of L-type channels did not produce the same effects. Further studies showed an induction of apoptosis by mibefradil or NNC treatment in a concentration-dependent manner. Studies into the mechanism of action of these inhibitors revealed their effect on metabolic pathways of MB cells. Our results present the first evidence to the antitumor effects of mibefradil and NNC in medulloblastoma cells. This study provides insight into the future development of potential therapeutic approaches for MB that target the invasion, proliferation, and drug resistance in these cells.