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T-type calcium channel inhibitors induce apoptosis in medulloblastoma cells associated with altered metabolic activity

Citation

Sedeeq, M and Maklad, A and Dutta, T and Feng, Z and Wilson, R and Gueven, N and Azimi, I, T-type calcium channel inhibitors induce apoptosis in medulloblastoma cells associated with altered metabolic activity, Molecular Neurobiology, 59 pp. 2932-2945. ISSN 0893-7648 (2022) [Refereed Article]


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The Author(s) 2022. his article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, (https://creativecommons.org/licenses/by/4.0/) which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

DOI: doi:10.1007/s12035-022-02771-0

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-550396 (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.

Item Details

Item Type:Refereed Article
Keywords:medulloblastoma, T-type calcium channels, mibefradil, NNC-55-0396, metabolic activity, apoptosis
Research Division:Biomedical and Clinical Sciences
Research Group:Pharmacology and pharmaceutical sciences
Research Field:Basic pharmacology
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the health sciences
UTAS Author:Sedeeq, M (Mr Mohammed Sedeeq)
UTAS Author:Maklad, A (Mr Ahmed Maklad)
UTAS Author:Feng, Z (Mr Zikai Feng)
UTAS Author:Wilson, R (Dr Richard Wilson)
UTAS Author:Gueven, N (Dr Nuri Guven)
UTAS Author:Azimi, I (Dr Iman Azimi)
ID Code:150812
Year Published:2022
Deposited By:Pharmacy
Deposited On:2022-07-01
Last Modified:2022-08-11
Downloads:0

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