Flavopiridol, a cyclin dependent kinase (CDK) inhibitor, induces apoptosis by regulating Bcl-x in oral cancer cells.
Flavopiridol is a synthetic flavone that inhibits tumor growth by suppressing cyclin-dependent kinases (CDKs). We have investigated effects of flavopiridol in oral squamous cell carcinoma (OSCC). Flavopiridol was found to inhibit the growth of OSCC cells in a time- and dose-dependent manner. Induction of apoptosis was observed in all cells showing accumulated cells with sub-G(1) DNA contents, DNA fragmentations, and PARP cleavages. While Bcl-2 and Bax expression did not change, Bcl-x(L) was down regulated and Bcl-xs was up-regulated after being exposed to flavopiridol. Flavopiridol treatments also resulted in remarkable reductions of cyclin A, cyclin B, and cyclin D1 expressions. We also found that expression levels of CDK activation kinase and CDC25C were reduced, and p34 inactive form CDK2 were up-regulated. Our data indicate that flavopiridol has growth inhibition activities against OSCC. Flavopiridol not only inhibits CDKs directly, but it also inhibits the CDKs activation pathway and activates the Bcl-x apoptotic pathway.
Mihara
Mariko
M
Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, Shigenobu, Ehime, 791-0295, Japan.
Shintani
Satoru
S
Nakashiro
Koh-ichi
K
Hamakawa
Hiroyuki
H
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005419:Flavonoids / Q000627:therapeutic use*; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010880:Piperidines / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C077990:alvocidib; D018844:Cyclin-Dependent Kinases