Abstract
5,5-diphenyl-2-thiohydantoin-N10 (DPTH-N10) is a synthetic derivative compound of anti-epileptic medicine phenytoin (5,5-diphenylhydantoin). Previously, we have shown that DPTH-N10 exerts an anti-angiogenesis activity. The aim of this study is to study the anti-proliferation effect of DPTH-N10 in colon cancer cells and its molecular mechanisms underlying. [3H]-Thymidine incorporation analysis demonstrated that DPTH-N10 at a range of concentrations (10-30 ?嵱) dose-dependently inhibited DNA synthesis in human colon cancer cell line (COLO-205). Western blot analysis showed that the p21 protein, a cell cycle inhibitory protein, increased significantly after treatment of COLO-205 cells with DPTH-N10 for 24 hours. In contrast, the protein levels of CDK2, CDK4, and Cyclins A, D1 and D3 were not changed significantly. Immuno-precipitation assay revealed that the protein-protein association between p21 and CDK2 was increased after DPTH-N10 treatment. Moreover, treatment of the COLO-205 with DPTH-N10 caused a decrease of the CDK2 kinase activity. Taken together, in COLO-205, DPTH-N10 up-regulates the expression of p21 protein, which in turn increases the CDK2/P21 association and decreases the CDK2 kinase activity, and finally causes cell cycle arrest at the G0/G1 phase. Due to the dual effects, including anti-angiogenesis and a direct inhibition of cancer cell proliferation, DPTH-N10 has a great potential to be developed as a new medicine for cancer treatment.
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