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

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.

• Authors: Jung Ok Ban, Ju Hoon Oh, Bang Yeon Hwang, Dong Cheul Moon, Heon-Sang Jeong, Seram Lee, Soyoun Kim, Hyosung Lee, Kyung-Bo Kim, Sang Bae Han, Jin Tae Hong
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 6 Pg. 1613-24 (Jun 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19509257 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Diterpenes, Kaurane (metabolism, 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, metabolism)
• NF-kappa B p50 Subunit (antagonists & inhibitors, genetics, 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