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Transcriptional CDK inhibitors CYC065 and THZ1 induce apoptosis in glioma stem cells derived from recurrent GBM

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Glioma stem cells (GSCs) are tumour initiating cells which contribute to treatment re-sistance, temozolomide (TMZ) chemotherapy and radiotherapy, in glioblastoma (GBM), the most aggressive adult brain tumour. A major contributor to the uncontrolled tumour cell proliferation in GBM is the hyper activation of cyclin‐dependent kinases (CDKs). Due to resistance to standard of care, GBMs relapse in almost all patients. Targeting GSCs using transcriptional CDK inhibitors, CYC065 and THZ1 is a potential novel treatment to prevent relapse of the tumour. TCGA‐GBM data analysis has shown that the GSC markers, CD133 and CD44 were significantly upregulated in GBM patient tumours compared to non‐tumour tissue. CD133 and CD44 stem cell markers were also expressed in gliomaspheres derived from recurrent GBM tumours. Light Sheet Florescence Microscopy (LSFM) further revealed heterogeneous expression of these GSC markers in glio-maspheres. Gliomaspheres from recurrent tumours were highly sensitive to transcriptional CDK inhibitors, CYC065 and THZ1 and underwent apoptosis while being resistant to TMZ. Apoptotic cell death in GSC subpopulations and non‐stem tumour cells resulted in sphere disruption. Collec-tively, our study highlights the potential of these novel CKIs to induce cell death in GSCs from recurrent tumours, warranting further clinical investigation.

Funding

GLIOTRAIN | Funder: EU Horizon 2020 | Grant ID: 766069

GLIOTRAIN PhD Support | Funder: RCSI | Grant ID: RCSI-GLIO-2020

Light Sheet Fluorescence Microscope (LSFM) for imaging of live and optically cleared biological samples | Funder: Science Foundation Ireland (SFI) | Grant ID: 16/RI/3740

FutureNeuro | Funder: Science Foundation Ireland (SFI) | Grant ID: 16/RC/3948

Irish Association for Cancer Research (IACR Educational Grant)

History

Associated research data files

Publicly available datasets were analyzed in this study. This data can be found here: http://gliovis.bioinfo.cnio.es/ (accessed on 23 April 2021).

Comments

The original article is available at https://www.mdpi.com/

Published Citation

Juric V. et al. Transcriptional CDK inhibitors CYC065 and THZ1 induce apoptosis in glioma stem cells derived from recurrent GBM. Cells. 2021;10(5):1182

Publication Date

12 May 2021

PubMed ID

34066147

Department/Unit

  • Centre for Systems Medicine
  • Physiology and Medical Physics

Research Area

  • Cancer
  • Neurological and Psychiatric Disorders

Publisher

MDPI

Version

  • Published Version (Version of Record)