Targeting cell cycle and apoptosis for the treatment of human malignancies.

Oncogenic transformation leads to cell cycle aberration and apoptosis dysregulation. Targeting cell cycle and apoptosis pathways has emerged as an attractive approach for the treatment of cancer. The activity of cdks can be modulated by targeting these kinases with small molecules that bind to the ATP binding pocket of cdks, or by altering the composition of the cdk/endogenous cdk inhibitor complexes by different mechanisms. Apoptosis can be modulated by targeting pro-apoptotic or pro-survival pathways. Several proteins relevant to oncogenic and proliferative processes, such as p53, bcl-2, AKT, ras and epidermal growth factor receptor, are also important in blocking apoptosis. Several small molecules that modulate cell cycle control and apoptosis have been approved recently and many will be approved in the near future. Several challenges remain, including finding ways of targeting these agents specifically to tumors (sparing normal cells), and the development of rationales for combining these new agents with standard therapies and for prioritizing the development of an overwhelming number of novel small molecules targeting cell cycle and apoptosis. Novel technologies such as genomics and proteomics will be instrumental in designing combinatorial regimens tailored to patients on the basis of the genetic makeup of tumors. Irrespective of all shortcomings, the future of modulation of apoptosis and cell cycle machinery for oncology therapy is quite exciting.