| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Cyclin-dependent kinases (CDKs) play an essential role in intracellular control of cell cycle. CDK inhinitors (Flavopiridol and Roscpvitine) that inhibits tumor growth in vitro and in vivo by because of the inhibiting CDKs. These agents are known to inhibit CDK2, CDK4 and CDK7 activities, to diminish cyclin Dl expressions, and to induce apoptosis. However, effects of CDK inhibitors against oral squamous cell carcinoma (OSCC) cells and mechanisms of these agents mediated cytotoxicity have not been fully elucidated.
In this study, we have investigated effects of CDK inhibitors in OSCC cell lines and studied mechanisms of CDK inhibitors mediated-apoptosis. CDK inhibitors were found to inhibit the growth of all five OSCC cells in time and dose-dependent manner and to diminish CDKs activities. Induction of apoptosis was observed in all cells, as well as cells with sub-Gl DNA contents, DNA fragmentations, and PARP cleavages. No alternation of expression levels of Bcl-2, an apoptosis regulator was observed. In contrast, Bcl-XL was down regulated and Bcl-Xs was up regulated after being exposed to CDK inhibitors. CDK inhibitors treatments also resulted in remarkable reductions of cyclin A, cyclin B, and cyclin Dl expressions in OSCC cells. We also found that expression levels of CDK Activation Kinase and CDC25C were reduced, and p34 CDK2 that phosphorylated in Thr 14 and Tyr 15: inactive form were up-regulated after CDK inhibitors exposure.
Our data indicate that CDK inhibitors has growth inhibition activities against OSCC in vitro. CDK inhibitors not only inhibits CDKs directly, but it also inhibits CDKs activation pathway and activates Bcl-X apoptotic pathway.
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