PXD026988

PXD026988 is an original dataset announced via ProteomeXchange.

Title	T-type calcium channel inhibitors induce apoptosis in medulloblastoma cells associated with altered metabolic activity
Description	Medulloblastoma (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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:45:08.071.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Richard Wilson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-29 03:02:50	ID requested
1	2023-04-26 18:04:33	announced
2	2023-11-14 08:45:10	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 05:45:08	announced	2024-10-22: Updated project metadata.

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;

submitter keyword: proteomics,Medulloblastoma, CaV3 inhibitors, calcium channels, apoptosis, therapy

Dr Richard Wilson
contact affiliation	Proteomics facility, Central Science Laboratory, University of Tasmania
contact email	richard.wilson@utas.edu.au
lab head
Richard Wilson
contact affiliation	University of Tasmania
contact email	richard.wilson@utas.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/04/PXD026988

PRIDE project URI

• PRIDE
  1. PXD026988
     1. Label: PRIDE project
     2. Name: T-type calcium channel inhibitors induce apoptosis in medulloblastoma cells associated with altered metabolic activity