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PXD026988

PXD026988 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleT-type calcium channel inhibitors induce apoptosis in medulloblastoma cells associated with altered metabolic activity
DescriptionMedulloblastoma (MB) is the most common malignant paediatric brain tumour. In our previous studies, we developed a novel 3D assay for MB cells and screened of plasma membrane calcium channel modulators. 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 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. 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 a synergistic 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.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:45:08.071.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterRichard Wilson
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-06-29 03:02:50ID requested
12023-04-26 18:04:33announced
22023-11-14 08:45:10announced2023-11-14: Updated project metadata.
32024-10-22 05:45:08announced2024-10-22: Updated project metadata.
Publication List
Sedeeq M, Maklad A, Dutta T, Feng Z, Wilson R, Gueven N, Azimi I, T-Type Calcium Channel Inhibitors Induce Apoptosis in Medulloblastoma Cells Associated with Altered Metabolic Activity. Mol Neurobiol, 59(5):2932-2945(2022) [pubmed]
10.1007/s12035-022-02771-0;
Keyword List
submitter keyword: proteomics,Medulloblastoma, CaV3 inhibitors, calcium channels, apoptosis, therapy
Contact List
Dr Richard Wilson
contact affiliationProteomics facility, Central Science Laboratory, University of Tasmania
contact emailrichard.wilson@utas.edu.au
lab head
Richard Wilson
contact affiliationUniversity of Tasmania
contact emailrichard.wilson@utas.edu.au
dataset submitter
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