Abstracts
1997 Digestive Disease Week

A novel strategy to inhibiting growth of human pancreatic cancer cells by blocking cyclin-dependent kinase activity.

H Iseki, TC Ko, X Xue, CM Townsend Jr. Department of Surgery, University of Texas Medical Branch, Galveston, TX.

Patients with pancreatic cancer have dismal prognosis with a 5-year survival rate of less than 5%. Conventional chemotherapy has been ineffective and novel strategies to control pancreatic tumor growth must be developed to improve overall survival. Cyclindependent kinases (Cdks) are a family of proteins that are activated during cell cycle progression and are essential for cell proliferation. Olomoucine and roscovitine are novel compounds that selectively inhibit Cdk2 kinase activity. This study was designed to examine whether olomoucine and roscovitine can block Cdk2 activity and inhibit proliferation of human pancreatic cancer cells. METHODS. Two human pancreatic carcinoma cell lines, BxPC-3 and CAV, were studied. Cells were plated in 5% serum (Control) and treated with olomoucine (30-300 µM) or roscovitine (3-30 µM). Cell numbers were counted by Coulter counter. Cdk2 activity was determined by first immunoprecipitating cellular proteins with anit-Cdk2 antiserum and measured for phosphorylation of Histone H1 protein in the presence or absence of Cdk inhibitors. RESULTS. Olomoucine and roscovitine inhibited proliferation of BxPC-3 and CAV cells on day 4 and day 6 (Fig. 1 [figure not available]) after treatment. This inhibitory effect was dosedependent and was observed as early as day 4 after treatment (Fig. 2 [figure not available]). Olomoucine and roscovitine blocked Cdk2 kinase activity of BxPC-3 and Cav cells (Fig. 3 [figure not available]). CONCLUSIONS. Our findings show that olomoucine and roscovitine are potent inhibitors of Cdk2 activity and cell proliferation in human pancreatic cancer cells. Inhibiting Cdk activity is a novel anti-tumor strategy with potential benefit for pancreatic cancers.