Inflexinol inhibits colon cancer cell growth through inhibition of nuclear factor-kappaB activity via direct interaction with p50

Mol Cancer Ther. 2009 Jun;8(6):1613-24. doi: 10.1158/1535-7163.MCT-08-0694. Epub 2009 Jun 9.

Abstract

Kaurane diterpene compounds have been known to be cytotoxic against several cancer cells through inhibition of nuclear factor-kappaB (NF-kappaB) activity. Here, we showed that inflexinol, a novel kaurane diterpene compound, inhibited the activity of NF-kappaB and its target gene expression as well as cancer cell growth through induction of apoptotic cell death in vitro and in vivo. These inhibitory effects on NF-kappaB activity and on cancer cell growth were suppressed by the reducing agents DTT and glutathione and were abrogated in the cells transfected with mutant p50 (C62S). Sol-gel biochip and surface plasmon resonance analysis showed that inflexinol binds to the p50 subunit of NF-kappaB. These results suggest that inflexinol inhibits colon cancer cell growth via induction of apoptotic cell death through inactivation of NF-kappaB by a direct modification of cysteine residue in the p50 subunit of NF-kappaB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Diterpenes, Kaurane / metabolism
  • Diterpenes, Kaurane / pharmacology*
  • Dose-Response Relationship, Drug
  • Electrophoretic Mobility Shift Assay
  • HCT116 Cells
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit / antagonists & inhibitors
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Diterpenes, Kaurane
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Proto-Oncogene Proteins c-bcl-2
  • ent-1,3,6,11-tetrahydroxykaur-16-ene-15-one 3,11-diacetate
  • Nitric Oxide Synthase Type II
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • Caspase 9