Cell Cycle as a Target of Antineoplastic Drugs

Abstract

The cell cycle consists of a number of complex biochemical pathways that ensure that the start of a particular event depends on the successful and right end of previous steps in the pathway. An important role is played by cyclin/cyclin-dependent kinase (cdk) complexes which are critical regulators of cell cycle progression and RNA transcription. To ensure proper progression through each phase, cells have developed a series of orchestrated checkpoints that govern the different cellular kinases required for distinct cell cycle events. In particular, several cell cycle protein kinases, including members of the Aurora family and the Polo-like kinases, play critical roles in mitotic entry and chromosome segregation that ensure the correct formation of daughter cells. Tumour cell proliferation is frequently associated to both genetic and epigenetic mechanisms commonly affecting the expression of cell cycle regulatory proteins or causing an incompetent checkpoint control, resulting in aberrant responses to cellular damage. These alterations result not only in proliferative advantages but also in an increased susceptibility to the accumulation of additional genetic alterations that contribute to tumour progression and acquisition of more aggressive phenotypes. In the last years, the identification of anticancer drugs directed against critical cell cycle regulators has received particular attention. Specifically, several preclinical and clinical trials are addressing cdks or cell cycle protein kinase inhibitors. Starting from a description of cell cycle, this review summarizes the most recent studies on drugs targeting cell cycle regulators that are being used in cancer therapy.