CDK Blockade Using AT7519 Suppresses Acute Myeloid Leukemia Cell Survival through the Inhibition of Autophagy and Intensifies the Anti-leukemic Effect of Arsenic Trioxide

The strong storyline behind the critical role of cyclin-dependent kinase (CDK) inhibitor proteinsin natural defense against malignant transformation not only represents a heroic perspective forthese proteins, but also provides a bright future for the application of small molecule inhibitorsof CDKs in the novel cancer treatment strategies. The results of the present study revealed thatthe inhibition of CDKs using pan-CDK inhibitor AT7519, as revealed by the induction of G1cell cycle arrest as well as the reduction of cyclins expression, resulted in decreased survival inacute myeloid leukemia (AML)-derived KG-1 cells, either in the context of single agent or incombination with arsenic trioxide (ATO). Apart from alterations in the expression of proliferationand apoptotic genes, the anti-survival property of AT7519 was coupled with the inhibition ofautophagy-related genes. Notably, we found that the blockage of autophagy system in KG-1cells resulted in a superior cytotoxic effect, introducing autophagy as a probable suppressor ofcell death. As far as we are aware, to date, no study has reported the contributory mechanismscorrelated with the less sensitivity of acute leukemia cells to AT7519 and our study suggested forthe first time that the activation of both PI3K and c-Myc signaling pathways could overshadow,at least partly, the efficacy of this agent in KG-1 cells. Overall, due to the pharmacologic safety ofAT7519, our study proposed this inhibitor as a promising agent for the treatment of AML eitheras a single agent or in a combined-modal strategy.