butyrolactone-i and Colonic-Neoplasms

CDK inhibitor, Butyrolactone I inhibited CDK1, 2 and 5 in CDKs. In syncronized human lung fibroblast WI38 cells, it inhibited G1/S transition by inhibiting the phosphorylation of RB protein and G2/M transition by inhibiting the phosphorylation of H1 histone. Also, it selectively inhibited the initiation of DNA replication. The MMP inhibitor, BE16627B, reversively inhibited metalloproteinases including MMPs. It showed the MMP-dependent inhibition of the growth and metastasis of human tumor cells in nude mice without any cytotoxicity and severe side effects. The MMP inhibitor, Marimastat, showed remarkable prolongation of the life span of patients with pancreatic tumors in clinical trials.

Topics: 4-Butyrolactone; Animals; Antineoplastic Agents; Colonic Neoplasms; Cyclin-Dependent Kinases; Dipeptides; Doxorubicin; Enzyme Inhibitors; Fibrosarcoma; Humans; Metalloendopeptidases; Mice; Mice, Nude; Protease Inhibitors; Succinates

Cyclin dependent kinases propel the cell cycle in collaboration with cyclins. We have examined the expression of cdk2/cdc2 in adenoma and focal carcinoma in adenomatous tissue to explore their role in tumorigenesis of colorectum. Immunohistochemical study revealed that cdk2/cdc2 was overexpressed in a subsets of adenoma (14/50; 28.0%) but this overexpression was much more obvious in focal carcinoma (13/15; 86.7%). These results suggest that cdk2/cdc2 is remarkably upregulated together with a malignant change. In an effort to demonstrate a significant role for cdk2/cdc2 in colon cancer, we investigated growth and apoptosis with butyrolactone I, a specific inhibitor for cdk2/cdc2, using 4 colon carcinoma cell lines (HCT116, LoVo, HT29, Colo 320DM). Butyrolactone I inhibited proliferation of all colon carcinoma cell lines at 100 microM and it induced apoptosis in LoVo cell line with induction of p53. Our findings suggest that inhibition of cdk2/cdc2 may be a useful strategy against colon cancer.

Topics: 4-Butyrolactone; Adenoma; Antineoplastic Agents; Apoptosis; Carcinoma; CDC2 Protein Kinase; CDC2-CDC28 Kinases; Cell Division; Colonic Neoplasms; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Enzyme Inhibitors; Humans; Protein Serine-Threonine Kinases; Tumor Cells, Cultured