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

J Gastrointest Surg. Jan-Feb 1998;2(1):36-43. doi: 10.1016/s1091-255x(98)80101-7.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • CDC2-CDC28 Kinases*
  • Cell Count
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • DNA, Neoplasm / analysis
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / therapeutic use*
  • Flow Cytometry
  • G1 Phase / drug effects
  • G1 Phase / genetics
  • Genes, p16 / genetics
  • Genes, p53 / genetics
  • Genes, ras / genetics
  • Growth Inhibitors / administration & dosage
  • Growth Inhibitors / therapeutic use*
  • Histones / metabolism
  • Humans
  • Kinetin
  • Mutation / genetics
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Purines / administration & dosage
  • Purines / therapeutic use*
  • Roscovitine
  • S Phase / drug effects
  • S Phase / genetics
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Growth Inhibitors
  • Histones
  • Purines
  • Roscovitine
  • olomoucine
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Kinetin