Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

Abstract

Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation.

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

“…Furthermore, paediatric tissues are more primed to apoptosis-inducing stimuli than corresponding adults [ 71 ] and more susceptible to damage. A potential solution is to indirectly target BCL-2 family proteins, for example with the CDK inhibitors Seliciclib [ 77 ], Dinaciclib [ 78 ], or THZ1 [ 67 ], which suppress MCL-1 levels. Secondly, ongoing development of more targeted inhibitors is addressing the lack of cancer-cell specificity of current BH3 mimetics.…”

Antiproliferative Activity of Gibbosic Acid H through Induction of G0/G1 Cell Cycle Arrest and Apoptosis in Human Lung Cancer Cells

“…CDKs play a critical role in regulating the cell cycle along with corresponding regulatory cyclins by controlling the progression of cells through the different stages of the cell cycle [ 29 , 30 ]. In particular, cyclin D1 is involved in the G 0 /G 1 cell cycle arrest, while cyclin E1 and CDK2 control the progression from the G 1 to the S phase.…”

Anti-Angiogenetic and Anti-Lymphangiogenic Effects of a Novel 2-Aminobenzimidazole Derivative, MFB

“…The mechanism of the difference in sensitivity of MFB between tumor cells and non-tumor Hacat keratinocytes remains to be investigated. It has been described that cell doubling time may affect sensitivity to chemotherapeutic agents ( 55 ). In addition, several studies have suggested that VEGFRs may be expressed by tumor cells, although VEGFRs are regarded as endothelial receptors.…”