Flavopiridol, the First Cyclin-Dependent Kinase Inhibitor: Recent Advances in Combination Chemotherapy

L.-M.      Wang; D.-M.      Ren

Abstract

The cell cycle is the series of events necessary for the division and duplication of a cell. The dysregulation of the cell cycle can promote the development of cancer. A group of proteins, cyclin-dependent kinases (CDKs), that control the cell cycle, provide new targets for treating cancer. As a result, cyclin-dependent kinase inhibitors (CDKIs) represent a novel class of chemotherapeutic agents. Of these, flavopiridol, a semisynthetic flavonoidal alkaloid, emerged as the first CDKI to enter clinical trials. Preclinical data indicate that flavopiridol could block the proliferation of neoplastic cells and induce programmed cell death as a single agent. Furthermore, recent emerging data revealed that flavopiridol can potentiate, generally in a dose- and sequence-dependent manner, the anti-tumor effects of many established chemotherapeutic agents. This review is primarily focused on the role of flavopiridol in combination with various therapeutic agents that are in or near clinical development.

Keywords: Anticancer, cancer, CDKIs, combination therapy, flavopiridol, flavonoid, Cyclin-Dependent Kinase Inhibitor, Combination Chemotherapy, Chemotherapeutic agents, Anti-tumor effects, Therapeutic agents, Mammalian enzyme systems, Dysoxylum binectariferum, Vascular endothelial growth factor (VEGF), Inhibit angiogenesis, Structure-activity relationships, Dose-limiting toxicities (DLT), Rohitukine, Oxoflavopiridols, P-TEFb, Adenine binding pocket, Pan-CDK inhibitors, Antiproliferative effect, Antiangiogenic effect, Flavopiridol's activation, Radiation-induced cytotoxicity, Docetaxel (FD), Histone Deacetylase Inhibitors (HDACIs), Cancer cell line OCA-I, Proteasome Inhibitors, Monoclonal Antibodies, Breast cancer mortality, T-cell leukemia, Gemcitabine, non-hematological malignancies, Antineoplastic agents, Gelatin microspheres (GMSs), Hyponatremia, thrombocytopenia, Neutropenia, Mitoxantrone, Humanized anti-Tac antibody, Histone deacetylase inhibitors, Hypoxia-inducible factor