A Novel Pentamethoxyflavone Down-Regulates Tumor Cell Survival and Proliferative and Angiogenic Gene Products through Inhibition of I kappa B Kinase Activation and Sensitizes Tumor Cells to Apoptosis by Cytokines and Chemotherapeutic Agents

作者：Phromnoi Kanokkarn; Reuter Simone; Sung Bokyung; Prasad Sahdeo; Kannappan Ramaswamy; Yadav Vivek R; Chanmahasathien Wisinee; Limtrakul Pornngarm; Aggarwal Bharat B^*

来源：Molecular Pharmacology, 2011, 79(2): 279-289.

DOI：10.1124/mol.110.067512

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-kappa B (NF-kappa B) pathway is linked to inflammation and tumorigenesis, we investigated the effect of PMF on this pathway. We found that PMF suppressed NF-kappa B 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-kappa B proteins to bind to DNA, it inhibited I kappa B alpha (inhibitory subunit of NF-kappa B) kinase, leading to suppression of phosphorylation and degradation of I kappa B alpha, and suppressed consequent p65 nuclear translocation, thus abrogating NF-kappa B-dependent reporter gene expression. Suppression of the NF-kappa B cell signaling pathway by the flavone led to the inhibition of expression of NF-kappa B-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-alpha and the chemotherapeutic agents cisplatin, paclitaxel, and 5-flurouracil. Overall, our results indicate that PMF suppresses the activation of NF-kappa B and NF-kappa B-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.

• 出版日期2011-2