Cyclin-dependent kinase and protein kinase C inhibitors: a novel class of antineoplastic agents in clinical development

Abstract

Malignant cells have acquired adaptations, which give them a growth and survival advantage over normal cells. One effect of many of these adaptations is that many cancerous cells are less likely to undergo programmed cell death (apoptosis) and, moreover, are resistant to chemotherapy-induced apoptosis. Other features of neoplastic cells are the loss of regulated or orderly progression through the cell cycle. In normal and cancerous cells, a balance between proapoptotic and antiapoptotic signals exists. Protein kinase C (PKC) is a cellular serine/threonine kinase with a central role in the mediation of mitogenic signals as well as the regulation of antiapoptotic signals. Inhibition of PKC by a novel group of chemical agents (PKC inhibitors) can induce apoptosis in some malignant cell lines, act as differentiating agents, and enhance the effect of cytotoxic chemotherapy. Other kinase inhibitors are potent inhibitors of kinases involved in the control of cell cycle progression (cyclin-dependent kinases [cdks]). Cdk inhibitors are able to induce cell cycle arrest in neoplastic cells and also act as enhancers of chemotherapy-induced apoptosis. The catalytic domain of different classes of kinases (PKC and cdk) share considerable homology. As a result, many kinase inhibitors that act by blocking the catalytic site are not highly specific and may act as inhibitors of both PKC and cdks. Preclinical studies point to potential applications for some of these PKC/cdk inhibitors, and current clinical trials are exploring the role these agents might have in cancer therapy. In this article, we discuss the rationale for the development of this novel class of agents and highlight those drugs, which have shown promise in clinical testing.