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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Blotting, Western
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Diterpenes, Kaurane / metabolism
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Diterpenes, Kaurane / pharmacology*
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Dose-Response Relationship, Drug
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Electrophoretic Mobility Shift Assay
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HCT116 Cells
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Humans
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Immunohistochemistry
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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NF-kappa B p50 Subunit / antagonists & inhibitors
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NF-kappa B p50 Subunit / genetics
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NF-kappa B p50 Subunit / metabolism*
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Binding
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Diterpenes, Kaurane
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NF-kappa B
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NF-kappa B p50 Subunit
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Proto-Oncogene Proteins c-bcl-2
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ent-1,3,6,11-tetrahydroxykaur-16-ene-15-one 3,11-diacetate
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Nitric Oxide Synthase Type II
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Poly(ADP-ribose) Polymerases
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Caspase 3
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Caspase 9