Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities.

The discussion on cell proliferation cannot be continued without taking a look at the cell cycle regulatory machinery. Cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs) are valuable members of this system and their equilibrium guarantees the proper progression of the cell cycle. As expected, any dysregulation in the expression or function of these components can provide a platform for excessive cell proliferation leading to tumorigenesis. The high frequency of CDK abnormalities in human cancers, together with their druggable structure has raised the possibility that perhaps designing a series of inhibitors targeting CDKs might be advantageous for restricting the survival of tumor cells; however, their application has faced a serious concern, since these groups of serine-threonine kinases possess non-canonical functions as well. In the present review, we aimed to take a look at the biology of CDKs and then magnify their contribution to tumorigenesis. Then, by arguing the bright and dark aspects of CDK inhibition in the treatment of human cancers, we intend to reach a consensus on the application of these inhibitors in clinical settings.

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 proteins in natural defense against malignant transformation not only represents a heroic perspective for these proteins, but also provides a bright future for the application of small molecule inhibitors of CDKs in the novel cancer treatment strategies. The results of the present study revealed that the inhibition of CDKs using pan-CDK inhibitor AT7519, as revealed by the induction of G1 cell cycle arrest as well as the reduction of cyclins expression, resulted in decreased survival in acute myeloid leukemia (AML)-derived KG-1 cells, either in the context of single agent or in combination with arsenic trioxide (ATO). Apart from alterations in the expression of proliferation and apoptotic genes, the anti-survival property of AT7519 was coupled with the inhibition of autophagy-related genes. Notably, we found that the blockage of autophagy system in KG-1 cells resulted in a superior cytotoxic effect, introducing autophagy as a probable suppressor of cell death. As far as we are aware, to date, no study has reported the contributory mechanisms correlated with the less sensitivity of acute leukemia cells to AT7519 and our study suggested for the 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 of AT7519, our study proposed this inhibitor as a promising agent for the treatment of AML either as a single agent or in a combined-modal strategy.