Abstract
Most anticancer drugs have their origin in traditional medicinal plants. We describe here a flavone, 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone (PMF), from the leaves of the Thai plant Gardenia obtusifolia, that has anti-inflammatory and anticancer potential. Because the nuclear factor-κB (NF-κB) pathway is linked to inflammation and tumorigenesis, we investigated the effect of PMF on this pathway. We found that PMF suppressed NF-κB activation induced by inflammatory agents, tumor promoters, and carcinogens. This suppression was not specific to the cell type. Although PMF did not directly modify the ability of NF-κB proteins to bind to DNA, it inhibited IκBα (inhibitory subunit of NF-κB) kinase, leading to suppression of phosphorylation and degradation of IκBα, and suppressed consequent p65 nuclear translocation, thus abrogating NF-κB-dependent reporter gene expression. Suppression of the NF-κB cell signaling pathway by the flavone led to the inhibition of expression of NF-κB-regulated gene products that mediate inflammation (cyclooxygenase-2), survival (XIAP, survivin, Bcl-xL, and cFLIP), proliferation (cyclin D1), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of antiapoptotic gene products by PMF correlated with the enhancement of apoptosis induced by tumor necrosis factor-α and the chemotherapeutic agents cisplatin, paclitaxel, and 5-flurouracil. Overall, our results indicate that PMF suppresses the activation of NF-κB and NF-κB-regulated gene expression, leading to the enhancement of apoptosis. This is the first report to demonstrate that this novel flavone has anti-inflammatory and anticancer effects by targeting the IKK complex.
Footnotes
- Received July 13, 2010.
- Accepted October 7, 2010.
This work was supported by the National Institutes of Health National Cancer Institute [Grants CA16672, CA124787-01A2]; the Center for Targeted Therapy of M. D. Anderson Cancer Center; and the Royal Golden Jubilee Scholarship for the PhD Program [Grant RGJ].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.067512.
ABBREVIATIONS:
- PMF
- pentamethoxyflavone (5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone)
- NF-κB
- nuclear factor-κB
- IκBα
- inhibitor of nuclear factor-κB α
- LPS
- lipopolysaccharide
- OA
- okadaic acid
- TNF
- tumor necrosis factor
- COX-2
- cyclooxygenase-2
- XIAP
- X-linked inhibitor of apoptosis protein
- cFLIP
- caspase-8 (FLICE)-like inhibitory protein
- MMP-9
- matrix metalloproteinase 9
- VEGF
- vascular endothelial growth factor
- IMDM
- Iscove's modified Dulbecco's medium
- FBS
- fetal bovine serum
- PARP
- poly(ADP-ribose) polymerase
- IKK
- IκB kinase
- EMSA
- electrophoretic mobility shift assay
- PAGE
- polyacrylamide gel electrophoresis
- TNFR
- TNF receptor
- TRADD
- TNFR-associated death domain
- TRAF2
- TNFR-associated factor 2
- NIK
- NF-κB-inducing kinase
- TAK
- transforming growth factor-β-activated kinase
- TAB1
- TAK-1 binding protein-1
- SEAP
- secretory alkaline phosphatase
- RIP
- receptor interacting protein
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- FITC
- fluorescein isothiocyanate
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- CSC
- cigarette smoke condensate
- ALLN
- N-acetyl-leucyl-leucyl-norleucinal
- PMA
- phorbol 12-myristate 13-acetate
- MDR
- multidrug resistance protein.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics