Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells
| Autor: | Dimitrios Solomos, Michela Garofalo, Alexander W I Cox, Ammara Mehmood, Caroline H Topham, Mattia Chiesa, Yuri D'Alessandra, Marta Buzzetti, Sonia Morlando, Gianpiero Di Leva |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Science
Pyridinium Compounds Palbociclib Article Cyclic N-Oxides chemistry.chemical_compound Downregulation and upregulation RZ medicine Humans Dinaciclib Protein Kinase Inhibitors Cancer Cell Proliferation Medulloblastoma Multidisciplinary Molecular medicine business.industry Indolizines R735 medicine.disease Cyclin-Dependent Kinases Neoplasm Proteins chemistry Apoptosis Cancer research Medicine Phosphorylation Cyclin-dependent kinase 9 Drug Screening Assays Antitumor business CDK inhibitor |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-16 (2021) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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