Abstract
Medulloblastoma (MB) is the most common malignant paediatric brain tumour. In our previous studies, we developed a novel 3D assay for MB cells that was used to screen a panel of plasma membrane calcium channel modulators for their effect on the 3D growth of D341 MB cells. These studies identified T-type (CaV3) channel inhibitors, mibefradil and NNC-55–0396 (NNC) as selective inhibitors of MB cell growth. Mibefradil was originally approved for the treatment of hypertension and angina pectoris, and recently successfully completed a phase I trial for recurrent high-grade glioma. NNC is an analogue of mibefradil with multiple advantages compared to mibefradil that makes it attractive for potential future clinical trials. T-type channels have a unique low voltage-dependent activation/inactivation, and many studies suggest that they have a direct regulatory role in controlling Ca2+ signalling in non-excitable tissues, including cancers. In our previous study, we also identified overexpression of CaV3.2 gene in MB tissues compared to normal brain tissues. In this study, we aimed to characterise the effect of mibefradil and NNC on MB cells and elucidate their mechanism of action. This study demonstrates that the induction of toxicity in MB cells is selective to T-type but not to L-type Ca2+ channel inhibitors. Addition of CaV3 inhibitors to vincristine sensitised MB cells to this MB chemotherapeutic agent, suggesting an additive effect. Furthermore, CaV3 inhibitors induced cell death in MB cells via apoptosis. Supported by proteomics data and cellular assays, apoptotic cell death was associated with reduced mitochondrial membrane potential and reduced ATP levels, which suggests that both compounds alter the metabolism of MB cells. This study offers new insights into the action of mibefradil and NNC and will pave the way to test these molecules or their analogues in pre-clinical MB models alone and in combination with vincristine to assess their suitability as a potential MB therapy.
Highlights
Medulloblastoma (MB) is a primary malignant tumour of the cerebellum that is rarely seen in adults and predominantly occurs in children
This study showed that CACNA1H (CaV3.2) gene was significantly upregulated in MB tissues compared to normal brain tissues, and its levels were associated with cancer metastasis and patients survival rates [8]
This study shows that CaV3 inhibitors, mibefradil and NNC, induce apoptosis that is associated with altered metabolic activity in MB cells
Summary
Medulloblastoma (MB) is a primary malignant tumour of the cerebellum that is rarely seen in adults and predominantly occurs in children. Current treatment options include a combined-modality approach of surgical resection, radio- and chemotherapy. Groups 3 and 4 tumours are associated with higher levels of metastasis and worse clinical outcomes than the other two groups [1]. Calcium signalling critically affects many cancer hallmarks, including cell proliferation, apoptosis resistance, metastasis and angiogenesis [3]. Many studies suggest that these channels have a direct regulatory role in controlling Ca2+ signalling in non-excitable cells, including some cancerous cells [5–7]. This study showed that CACNA1H (CaV3.2) gene was significantly upregulated in MB tissues compared to normal brain tissues, and its levels were associated with cancer metastasis and patients survival rates [8]. This study suggested the potential importance of this Ca2+ channel in MB progression
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