Promotion of Apoptosis in Cancer Cells by Selective Purine-Derived Pharmacological CDK Inhibitors: One Outcome, Many Mechanisms

Jozefa      Wasierska-Gadek; Margarita      Maurer

Abstract

The deregulation of apoptosis and the cell cycle are important steps in the onset of cancer, giving cells unlimited reproductive potential and increasing their likelihood of survival. The cell cycle is an essential and tightly regulated four-stage process that effects the accurate duplication and transmission of genetic content to cells progeny. Cyclin-dependent kinases (CDKs) are key elements of the mammalian cell cycle machinery. Their activity is normally regulated via cyclin binding, phosphorylation events, and interactions with endogenous CDK inhibitors. Malfunctions in the control of the cell cycle can be specifically countered using pharmacological CDK inhibitors. Importantly, CDK inhibitors are very effective against both rapidly dividing and quiescent cancer cells; this is particularly relevant in the treatment of malignancies such as chronic lymphatic leukemia (CLL) and multiple myeloma (MM) that exhibit both a low mitotic index and apoptotic defects. The high efficacy of pharmacological CDK inhibitors against CLL and MM is attributable to their ability to eliminate leukemic cells by apoptosis. Indeed, not only do pharmacological CDK inhibitors block cell cycle progression; they also promote apoptosis and thereby destroy irrevocably malignant cells. This article focuses on the impact of inhibiting individual cellular CDKs on apoptosis. We discuss in detail the molecular mechanisms by which CDK inhibitors are able to bypass chemoresistance in tumor cells and trigger apoptosis. Remarkably, recent findings suggest that the pharmacological utility of CDK inhibitors may not be restricted to the treatment of cancer: some may be efficacious in the treatment of patients with neurodegenerative and cardiovascular diseases.

Keywords: p53-dependent apoptosis, survivin, IAPs, CDK7, CDK9, RNAP II, G2 cell cycle arrest, transcriptional elongation