Induction of differentiation of colon cancer cells by combined inhibition of kinases and histone deacetylase

Anticancer Res. Mar-Apr 2007;27(2):741-8.


The MAP kinase pathway inhibitor U0126 in combination with butyrate promotes differentiation in some colon cancer cell lines. We examined several inhibitors of histone deacetylase (HDAC) in combination with U0126 and other protein kinase inhibitors to see if these effects are general properties of HDAC inhibitors or butyrate alone. Alkaline phosphatase and peptidase activities were examined as markers for cellular differentiation in the human colon cancer cell lines Caco-2 and HT29 and the minimally transformed NCM460. Several HDAC inhibitors caused greater increases of alkaline phosphatase in the cancer cells than in NCM460, in which butyrate was the only HDAC inhibitor that caused a consistent increase. Unlike the JNK and PKC inhibitors examined, the MEK 1/2 inhibitor U0126 induced alkaline phosphatase activity in Caco-2 as a single agent and caused additive effects with HDAC inhibitors. The PI-3 kinase inhibitor LY294002 had little effect alone but enhanced the response of most HDAC inhibitors as did the raf inhibitor GW5074. In addition to butyrate, several HDAC inhibitors can induce differentiation in colon cancer cells and the responses may be enhanced by U0126, GW5074 and LY294002.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / biosynthesis
  • Butadienes / pharmacology
  • Caco-2 Cells
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Chromones / pharmacology
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / pathology
  • Drug Synergism
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology*
  • HT29 Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • Morpholines / pharmacology
  • Nitriles / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase Inhibitors / pharmacology*
  • Sulfhydryl Compounds / pharmacology


  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Morpholines
  • Nitriles
  • Protein Kinase Inhibitors
  • Sulfhydryl Compounds
  • U 0126
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • MAP2K2 protein, human
  • Protein Kinase C
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Alkaline Phosphatase