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

Abstract

Most anticancer drugs have their origin in traditional medicinal plants. We describe here a flavone, 5,3Ј-dihydroxy-3,6,7,8,4Ј-pentamethoxyflavone (PMF), from the leaves of the Thai plant Gardenia obtusifolia, that has anti-inflammatory and anticancer potential. Because the nuclear factor-B (NF-B) pathway is linked to inflammation and tumorigenesis, we investigated the effect of PMF on this pathway. We found that PMF suppressed NF-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-〉 proteins to bind to DNA, it inhibited IB␣ (inhibitory subunit of NF-B) kinase, leading to suppression of phosphorylation and degradation of IB␣, and suppressed consequent p65 nuclear translocation, thus abrogating NF-B-dependent reporter gene expression.Suppression of the NF-B cell signaling pathway by the flavone led to the inhibition of expression of NF-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-␣ and the chemotherapeutic agents cisplatin, paclitaxel, and 5-flurouracil. Overall, our results indicate that PMF suppresses the activation of NF-B and NF-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.

Disease chemopreventive effects and molecular mechanisms of hydroxylated polymethoxyflavones

“…They found that 5,3′‐dihydroxy‐3,6,7,8,4′‐pentamethoxyflavone induces apoptosis through multiple mechanism including down‐regulation of anti‐apoptotic factors (XIAP, cFLIP, Mcl‐1, Bcl‐2, and Bcl‐XL), induction of CDK inhibitors (p21 and p27), activation of caspases and inhibition of PI3K/AKT/GSK3β signaling . Moreover, 5,3′‐dihydroxy‐3,6,7,8,4′‐pentamethoxyflavone was found to sensitize cancer cell death caused by tumor necrosis factor‐α (TNF‐α) and chemotherapeutic drugs by targeting IKK and thus further abrogating the function of nuclear factor‐κB (NF‐κB) . 5,3′‐Dihydroxy‐3,6,7,8,4′‐pentamethoxyflavone was also reported to inhibit STAT3 activation not only through targeting multiple upstream kinases (JAK1, JAK2, Akt, and EGFR) but also through tyrosine phosphatase SHP‐1, which acts to de‐phosphorylate STAT3.…”

Dihydroxypentamethoxyflavone Down-Regulates Constitutive and Inducible Signal Transducers and Activators of Transcription-3 through the Induction of Tyrosine Phosphatase SHP-1

“…Extracts of this plant are used to inhibit implantation (Luechtefeld et al, 1981) and suppress ulcers (Takase et al, 1989) and as an antibacterial agent (Laurens et al, 1985). One of the compounds isolated from this plant, 5, 6,7,8,, is cytotoxic to various cancer cell lines (Lichius et al, 1994;Shi et al, 1995;Zhang et al, 1999), exhibits anti-HIV activity (Tuchinda et al, 2004), is a potent inducer of apoptosis and abrogates the nuclear factor-B cell signaling pathway (Phromnoi et al, 2011). PMF isolated from another medicinal plant, Polanisia dodecandra (native to North America), has been reported to exhibit anticancer activity by binding to tubulin and inhibiting its polymerization (Lichius et al, 1994;Shi et al, 1995;Zhang et al, 1999).…”