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

Abstract

Pancreatic cancers frequently carry mutations in the K- ras, p53, and p16 genes, which regulate cell proliferation. Transition from G1 to S phase of the cell cycle requires activation of cyclin-dependent kinase 2 (Cdk2), which is inhibited by olomoucine and roscovitine. The purpose of this study was to determine whether olomoucine and roscovitine can block Cdk2 kinase activity and inhibit proliferation of four human pancreatic cancer cell lines with various genetic alterations. Human pancreatic carcinoma cell lines BxPC-3, PANC-1, Capan-2, and CAV were treated with olomoucine or roscovitine. Cdk2 kinase activity was determined using histone H1 as the substrate. Cell cycle distribution was analyzed by DNA flow cytometry. Cell numbers were quantitated by Coulter counter. Olomoucine and roscovitine blocked Cdk2 activity in all four pancreatic cancer cell lines. Both compounds also inhibited cell proliferation in a dose-dependent fashion. Roscovitine was at least threefold more potent than olomoucine for both Cdk2 activity and cell proliferation. We have shown that Cdk inhibitors, olomoucine and roscovitine, block proliferation of human pancreatic cancer cells regardless of their mutations in K- ras, p53, or p16 genes. These compounds represent a novel therapeutic strategy with potential therapeutic benefits for pancreatic cancers.