Cyclin-dependent kinase inhibitor (roscovitine) suppresses growth and induces apoptosis by regulating Bcl-x in head and neck squamous cell carcinoma cells.
Cyclin-dependent kinases (Cdks) play essential roles in the intracellular controls of the cell cycles. Roscovitine, [2-(R)-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine], is a potent and selective inhibitor of the Cdk2 and Cdc2. We investigated whether this compound was effective against head and neck squamous cell carcinoma (HNSCC) cells. Roscovitine was found to inhibit the growth of all 11 HNSCC cell lines in time- and dose-dependent manner and to diminish the Cdk2 and Cdc2 activities. An induction of apoptosis was observed in all cells, as judged by the cell morphology, along with the appearance of cells with sub-G1 DNA contents, DNA fragmentations, and poly(ADP-ribose) polymerase (PARP) cleavage. In four HNSCC cell lines, apoptosis was induced without antecedent marked cell cycle arrest, and in the other seven cell lines, cell cycle arrest preceded cell death. We also found up-regulation of Bcl-xS in the former cell lines, and in the latter cell lines, the expressions of Bcl-2 and Bcl-xL were induced simultaneously. These results suggest that roscovitine exerts antitumor activities in HNSCC and is associated with induction of Bcl-xS. Roscovitine can be considered to provide a new chemopreventive and chemotherapeutic strategy for the clinical management of HNSCC.
Mihara
Mariko
M
Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, Ehime 791-0295, Japan. mmariko@m.ehime-u.ac.jp
Shintani
Satoru
S
Kiyota
Akihisa
A
Matsumura
Tomohiro
T
Wong
David T W
DT
D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D016213:Cyclins; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D051020:bcl-X Protein; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases