@article {Phromnoimol.110.067512, author = {Kanokkarn Phromnoi and Simone Reuter and Bokyung Sung and Sahdeo Prasad and Ramaswamy Kannappan and Vivek R Yadav and Wisinee Chanmahasathien and Pornngarm Limtrakul and Bharat B Aggarwal}, title = {A Novel Pentamethoxyflavone Downregulates Tumor Cell Survival, Proliferative, and Angiogenic Gene Products Through Inhibition of Activation of IκB Kinase, and Sensitizes Tumor Cells to Apoptosis by Cytokines and Chemotherapeutic Agents}, elocation-id = {mol.110.067512}, year = {2010}, doi = {10.1124/mol.110.067512}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Most anticancer drugs have their origin in traditional medicinal plants. We describe here a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,3{\textquoteright}-dihydroxy-3,6,7,8,4{\textquoteright}-pentamethoxyflavone (PMF), that has anti-inflammatory and anticancer potential. Because the nuclear factor-kappaB (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-κΒ proteins to bind to DNA, it inhibited IκBα (inhibitory subunit of NF-κB) kinase, leading to suppression of phosphorylation and degradation of IκBα, 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 (cyclinD1), 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 (TNF)-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 anti-cancer effects by targeting the IKK complex.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2010/10/07/mol.110.067512}, eprint = {https://molpharm.aspetjournals.org/content/early/2010/10/07/mol.110.067512.full.pdf}, journal = {Molecular Pharmacology} }