Conversion of Drug-Induced Differentiation to Apoptosis by Pharmacologic Cyclin-Dependent Kinase Inhibitors

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Abstract
Recently, considerable attention has focused on the clinical development of novel anticancer agents which are intended to induce differentiation (i.e., protein kinase C activators and histone deacetylase inhibitors) or to inhibit cyclin-dependent kinases (CDKs) (i.e., flavopiridol and UCN-01). Because the differentiation process requires cell cycle arrest (e.g., in G(1)), the possibility arises that CDK inhibitors might potentiate the maturation response of neoplastic cells to various differentiation-inducing agents. However, recent findings indicate that contrary to expectations, pharmacologic CDK inhibitors fail to promote differentiation, at least in human leukemia cells; instead, they antagonize the maturation process and induce dysregulation of various cell cycle and apoptotic regulatory proteins that culminate in mitochondrial injury and apoptosis. A brief summary of the events that might contribute to these phenomena in human leukemia cells follows below. A better understanding of interactions between putative differentiation-inducers and cell cycle inhibitors may provide the foundation for the future development of novel chemotherapeutic strategies in hematopoietic and possibly non-hematopoietic malignancies.

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