P04.11 Profound sensitivity of glioblastoma cells to apoptosis induction by TG02, a novel oral multi-cyclin-dependent kinase inhibitor
| Autor: | Michael Weller, E Le Rhun, Manuela Silginer, Birthe Lohmann, Emese Szabo, Hannah Schneider, K Meetze, C von Achenbach |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Europe PubMed Central |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noy139.245 |
| Popis: | BACKGROUND: TG02 is a novel multikinase inhibitor targeting cyclin-dependent kinases (CDK) -1, -2, -5, -7 and -9 and thought to act mainly via CDK-9 inhibition-dependent depletion of short-lived oncoproteins such as MCL-1 or c-MYC. MATERIAL AND METHODS: We studied the activity of TG02 in 9 human long-term glioma cell lines (LTC) and 5 glioma-initiating cell lines (GIC) using various cell death assays in vitro and in the ZH-161 GIC model in vivo. RESULTS: TG02 exhibits strong anti-tumor cell activity with EC(50) concentrations in the nanomolar range. Median survival in the ZH-161 model was prolonged by TG02 from 28 to 33 days (p=0.056). Neither constitutive CDK levels nor those of MCL-1 or c-MYC correlated with sensitivity to TG02. Cdk-9 or cdk-5 gene silencing alone did not fully reproduce the effects of TG02. C-myc gene silencing inhibited cell growth, but did not affect TG02 activity. High concentrations of TG02 induced annexin V binding and minor caspase 3 cleavage, and the pan-caspase inhibitor, zVAD-fmk, or BCL-2 or MCL-1 gene transfer moderately attenuated TG02-induced cell death; still, electron microscopy revealed cell death to be essentially apoptotic. TG02 activity was independent of O(6)-methylguanine DNA methyltransferase expression. Repetitive exposure to TG02 did not generate an acquired TG02 resistance phenotype, but accumulation of MCL-1, loss of c-MYC, or senescence. CONCLUSION: TG02 is a highly potent anti-glioma agent in vitro that appears to induce cell death mainly in an apoptotic, but largely caspase-independent manner. Clinical evaluation of TG02 in glioblastoma is warranted. |
| Databáze: | OpenAIRE |
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