Anticancer drug targets: cell cycle and checkpoint control

Abstract

Components of the cell cycle machinery are frequently altered in human cancer. Central players are the cyclin-dependent kinases (cdks), which govern the initiation, progression, and completion of cell cycle events. The scheduled activity of the cdks, which allows orderly transition between cell cycle phases, is controlled by their association with cyclins and cdk inhibitors, by their state of phosphorylation, and by ubiquitin-mediated proteolysis. As malignant cells evolve, both genetic and epigenetic mechanisms commonly affect the expression of cell cycle regulatory proteins, causing overexpression of cyclins and loss of expression of cdk inhibitors. A major consequence is deregulated cdk activity, providing cells with a selective growth advantage. The crucial role of the cdks has prompted great interest in the development of specific kinase inhibitors that would be expected to block cell cycle progression and induce growth arrest. Another hallmark of the transformed state is incompetent checkpoint control, resulting in aberrant responses to cellular damage. For example, damage to DNA or the spindle apparatus normally triggers cell cycle arrest or apoptosis, depending on the degree of damage and the cellular context. Cell cycle arrest most frequently occurs at the G1/S or G2/M boundaries. When checkpoint arrest control is compromised, initiation of S phase or mitosis occurs despite cellular damage, and the ensuing genetic instability may lead to the eventual emergence of a malignant clone. However, this failure of cell cycle arrest responses in malignant cells can also be exploited therapeutically. Cells in which checkpoint control is disrupted are more sensitive to additional genotoxic or microtubular damage. Unbridled cell cycle progression in the presence of such damage is usually lethal, which may explain the selective sensitivity of some cancer cells to DNA-damaging treatments. For this reason, intact components of cell cycle arrest checkpoints are also potential targets for novel antineoplastics, and their inhibition may increase the sensitivity of tumor cells to standard chemotherapy and radiation (1). Many of the compounds under study as anti-tumor agents act at multiple steps in the cell cycle, and their effects may be cytostatic or cytotoxic, depending on the cell cycle status of the target cells. Hence, an understanding of the molecular interactions involved may suggest ways to sensitize cells to the effects of these compounds. In particular, combinations of drugs, applied in a specific sequence, may be used to maneuver a tumor cell population into a state where it is most susceptible to the cytotoxic effects of novel, or indeed traditional, chemotherapeutic agents. Here, we review key aspects of cell cycle and checkpoint control, as well as exploitable abnormalities commonly found in cancer, in order to focus on promising targets of new agents presently in clinical trial or under development.