Conversion of drug-induced differentiation to apoptosis by pharmacologic cyclin-dependent kinase inhibitors.
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.
Grant
Steven
S
Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, USA. stgrant@hsc.vcu.edu
Dent
Paul
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology*
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases