Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells
Authors
Buzzetti, MartaMorlando, S.
Solomos, D.
Mehmood, A.
Cox, A. W. I.
Chiesa, M.
D'Alessandra, Y.
Garofalo, Michela
Topham, C. H.
Di Leva, G.
Affiliation
School of Science, Engineering and Environment, Biomedical Research Centre, Salford, Greater Manchester, UK.Issue Date
2021
Metadata
Show full item recordAbstract
Medulloblastoma (MB) is the most common aggressive paediatric brain tumour and, despite the recent progress in the treatments of MB patients, there is still an urgent need of complementary or alternative therapeutic options for MB infants. Cyclin Dependent Kinase inhibitors (CDKi) are at the front-line of novel targeted treatments for multiple cancers and the CDK4/6 specific inhibitor palbociclib has been pre-clinically identified as an effective option for MB cells. Herein, we identified the pan-CDKi dinaciclib as a promising alternative to palbociclib for the suppression of MB cells proliferation. We present evidence supporting dinaciclib's ability to inhibit MB cells in vitro proliferation at considerably lower doses than palbociclib. Sequencing data and pathway analysis suggested that dinaciclib is a potent cell death inducer in MB cells. We found that dinaciclib-triggered apoptosis is triggered by CDK9 inhibition and the resultant reduction in RNA pol II phosphorylation, which leads to the downregulation of the oncogenic marker MYC, and the anti-apoptotic protein MCL-1. Specifically, we demonstrated that MCL-1 is a key apoptotic mediator for MB cells and co-treatment of dinaciclib with BH3 mimetics boosts the therapeutic efficacy of dinaciclib. Together, these findings highlight the potential of multi-CDK inhibition by dinaciclib as an alternative option to CDK4/6 specific inhibition, frequently associated with drug resistance in patients.Citation
Buzzetti M, Morlando S, Solomos D, Mehmood A, Cox AWI, Chiesa M, et al. Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells. Sci Rep. 2021;11(1):5374.Journal
Science ReportsDOI
10.1038/s41598-021-84082-3PubMed ID
33686114Additional Links
https://dx.doi.org/10.1038/s41598-021-84082-3Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41598-021-84082-3
Scopus Count
Collections
Related articles
- Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors.
- Authors: Abdalla AN, Abdallah ME, Aslam A, Bader A, Vassallo A, Tommasi N, Malki WH, Gouda AM, Mukhtar MH, El-Readi MZ, Alkahtani HM, Abdel-Aziz AA, El-Azab AS
- Issue date: 2020 May 8
- Dinaciclib Interrupts Cell Cycle and Induces Apoptosis in Oral Squamous Cell Carcinoma: Mechanistic Insights and Therapeutic Potential.
- Authors: Oner M, Cheng YC, Soong SW, Cheng PT, Wang YH, Yang SF, Tsai SC, Lin H
- Issue date: 2025 Feb 28
- The Cdk inhibitor dinaciclib as a promising anti-tumorigenic agent in biliary tract cancer.
- Authors: Ablinger C, Neureiter D, Mähr T, Mayr C, Kiesslich T, Maeding N, Valenta I, Ardelt M, Wilhelm F, Neureiter E, Ritter M, Pachmayr J, Huber-Cantonati P
- Issue date: 2024 Dec 31
- Dinaciclib, a cyclin-dependent kinase inhibitor, suppresses cholangiocarcinoma growth by targeting CDK2/5/9.
- Authors: Saqub H, Proetsch-Gugerbauer H, Bezrookove V, Nosrati M, Vaquero EM, de Semir D, Ice RJ, McAllister S, Soroceanu L, Kashani-Sabet M, Osorio R, Dar AA
- Issue date: 2020 Oct 28
- Anti-Tumor and Chemosensitizing Effects of the CDK Inhibitor Dinaciclib on Cholangiocarcinoma In Vitro and In Vivo.
- Authors: Sungwan P, Kidoikhammouan S, Thonsri U, Saengboonmee C, Wongkham S, Okada S, Seubwai W
- Issue date: 2024 Sep-Oct