title: Flavopiridol enhances human tumor cell radiosensitivity and prolongs expression of gammaH2AX foci.
abstract: Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor, which has recently entered clinical trials. However, when administered as a single agent against solid tumors, the antitumor actions of flavopiridol have been primarily cytostatic. Given its reported effects on cell cycle regulation, transcription, and apoptosis, flavopiridol may also influence cellular radioresponse. Thus, to evaluate the potential for combining this cyclin-dependent kinase inhibitor with radiation as a cancer treatment strategy, we have investigated the effects of flavopiridol on the radiation sensitivity of two human prostate cancer cell lines (DU145 and PC3). The data presented here indicate that exposure to flavopiridol (60-90 nM) after irradiation enhanced the radiosensitivity of both DU145 and PC3 cells. This sensitization occurred in the absence of significant reductions in cell proliferation, retinoblastoma protein phosphorylation, or P-TEFb activity. Moreover, the post-irradiation addition of flavopiridol had no effect on radiation-induced apoptosis or the activation of the G2 cell cycle checkpoint. However, flavopiridol did modify the time course of gammaH2AX expression in irradiated cells. Whereas there was no significant difference in radiation-induced gammaH2AX foci at 6 h, at 24 h after irradiation, the number of cells expressing gammaH2AX foci was significantly greater in the flavopiridol-treated cells. These results indicate that flavopiridol can enhance radiosensitivity of human tumor cells and suggest that this effect may involve an inhibition of DNA repair.
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Brady
authors.forename: William E
authors.initials: WE
authors.lastname: Burgan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cerra
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Russell
authors.forename: Elizabeth E A
authors.initials: EE
authors.lastname: Bull
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Tofilon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D019938:Cyclin D1 / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; C468783:H2AX protein, human; D006657:Histones; D010880:Piperidines; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C077990:alvocidib; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II