epidermal-growth-factor and myricetin

Myricetin is a naturally omnipresent benzo-α-pyrone flavonoids derivative; has potent anticancer activity. Receptor tyrosine kinases family provides the decisive role in cancer initiation and progression. These receptors have recently caught the attention of the researchers as an attractive target to combat cancer, owing to the evidences endorsed their over-expression on cancer cells. This study is a concerted effort to explore the potent and specific multi-targeted inhibitor against RTKs and AR\\ER employing molecular docking approach. IR, IGF1R, EGFR, VEGFR1, VEGFR2, and AR\\ER were chosen as a protein and natural compounds as a ligand. Molecular docking procedure followed by using Maestro 9.6 (Schrödinger Inc). All natural compounds were docked with the X-ray crystal structures of selected proteins by employing grid-based ligand docking with energetics Maestro 9.6. IBS natural compounds docked with each selected protein molecules by using GLIDE high throughput virtual screening. On the basis of Gscore, we selected 20 compounds from IBS (50,000 compounds) along with 68 anticancer compounds from published literature for GLIDE extra precision molecular docking. Calculated docking free energy yielded the excellent dock score for the myricetin when docked with proteins EGFR, IR, and AR\\ER. Protein-ligand interactions profile highlighted that the lipophilic, hydrogen bonding and π-π stacking interactions play a central role in protein-ligand interactions at the active site. The results of MTT assay reveal that the myricetin inhibit the viability and proliferation of cancer cells in a dose-dependent manner. Treatment with the myricetin led to down-regulation of mRNA expression of EGFR, IR, mTOR, and Bcl-2. Although, further in vitro and in vivo experimental studies are required for the experimental validation of our findings.

Topics: Androgen Receptor Antagonists; Cell Line, Tumor; Cell Movement; Cell Proliferation; Computer Simulation; Databases, Chemical; Drug Evaluation, Preclinical; Epidermal Growth Factor; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Insulin; Insulin Antagonists; Ligands; Molecular Docking Simulation; Reactive Oxygen Species; Receptors, Androgen; Receptors, Estrogen; RNA, Messenger; Software; Thermodynamics

JAK1/STAT3 pathway has been suggested to play a role in cell transformation and carcinogenesis. In the present study, we found that myricetin (3, 3', 4', 5, 5', 7-hexahydroxyflavone), a typical flavonol existing in many fruits and vegetables, could directly bind to JAK1/STAT3 molecules to inhibit cell transformation in epidermal growth factor (EGF)-activated mouse JB6 P(+) cells. Colony assay revealed that myricetin had the strongest inhibitory effect on cell transformation among three flavonols including myricetin, quercetin and kaempferol. Molecular data revealed that myricetin inhibited DNA- binding and transcriptional activity of STAT3. Furthermore, myricetin inhibited the phosphorylation of STAT3 at Tyr705 and Ser727. Cellular signaling analyses revealed that EGF could induce the phosphorylation of Janus Kinase (JAK) 1, but not JAK2. Myricetin inhibited the phosphorylation of JAK1 and increased the autophosphorylation of EGF receptor (EGFR). Moreover, ex vivo and in vitro pull-down assay revealed that myricetin bound to JAK1 and STAT3, but not EGFR. Affinity data further demonstrated that myricetin had a higher affinity for JAK1 than STAT3. Thus, our data indicate that myricetin might directly target JAK1 to block cell transformation in mouse JB6 cells.

Topics: Animals; Antioxidants; Cell Line; Cell Transformation, Neoplastic; DNA; Epidermal Growth Factor; Flavonoids; Janus Kinase 1; Kaempferols; Mice; Phosphorylation; Protein Binding; Quercetin; STAT3 Transcription Factor; Transcription, Genetic

Evidence suggests that mitogen-activated protein kinase kinase (MEK) plays a role in cell transformation and tumor development and might be a significant target for chemoprevention. 3,5,4'-Trihydroxy-trans-stilbene (resveratrol), a non-flavonoid polyphenol found in various foods and beverages, including red wines, is reported to be a natural chemopreventive agent. However, the concentrations required to exert these effects might be difficult to achieve by drinking only one or two glasses of red wine a day. On the other hand, the flavonol content of red wine is approximately 30 times higher than that of resveratrol. Here we demonstrated that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal cells. Myricetin (10 microM) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA) or epidermal growth factor (EGF)-induced cell transformation by 76 or 72%, respectively, compared with respective reductions of 26 or 19% by resveratrol (20 microM). A combination of myricetin and resveratrol exerted additive but not synergistic effects on either TPA- or EGF-induced transformation. Myricetin, but not resveratrol, attenuated tumor promoter-induced activation of c-fos or activator protein-1. Myricetin strongly inhibited MEK1 kinase activity and suppressed TPA- or EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) or p90 ribosomal S6 kinase, downstream targets of MEK. Moreover, myricetin inhibited H-Ras-induced cell transformation more effectively than either PD098059, a MEK inhibitor, or resveratrol. Myricetin directly bound with glutathione S-transferase-MEK1 but did not compete with ATP. Overall, these results indicated that myricetin has potent anticancer-promoting activity and mainly targets MEK signaling, which may contribute to the chemopreventive potential of several foods including red wines.

Topics: Animals; Antineoplastic Agents; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Enzyme Inhibitors; Epidermal Growth Factor; Fireflies; Flavonoids; Genes, Reporter; Luciferases; MAP Kinase Kinase 1; Mice; Recombinant Proteins; Tetradecanoylphorbol Acetate