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- W2898890640 abstract "Background Melanoma is a reactive oxygen species (ROS)-driven cancer but developing antioxidants as therapeutic drugs have not been successful. Methods We screened a number of antioxidants for their capacity of inhibiting melanoma cell growth and identified luteolin and honokiol as the best candidates. A series of molecular studies were performed in order to delineate the mechanism of action for luteolin. Results Luteolin unexpectedly induced ROS at its IC50 range of concentrations; co-treatment with antioxidants NAC or mito-TEMPO did not rescue cell growth inhibition, although ROS levels were reduced. Luteolin also inhibited PDE4B and AKT kinase pathways, but over-expression of AKT2 or AKT3 did not show a significant effect on reversing the growth inhibition in vitro. Luteolin showed strong inhibition on BRAF kinase at protein and mRNA levels, accompanied by lower levels of phosphorylated MEK1/2 and ERK1/2 kinases. The BRAF mutation status did not show a difference towards luteolin effect. Over-expression of mutant BRAF (BRAFV600E) in A375 or wild-type BRAF in WM3211 cells reversed the luteolin-induced cell growth inhibition. An in silica pharmacophore mapping revealed that BRAF protein is an excellent target for luteolin. Subsequent protein-ligand docking modeling has revealed that luteolin binds to BRAF through Cys531, a potential redox-sensitive residue that is located in the ATP-binding pocket. Further studies revealed that as a single agent luteolin effectively inhibited melanoma tumor growth in vivo. Conclusion BRAF may be a crucial and direct target for luteolin, which explains the outstanding inhibitory effect of luteolin in multiple cancer types." @default.
- W2898890640 created "2018-11-09" @default.
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- W2898890640 date "2018-11-01" @default.
- W2898890640 modified "2023-09-27" @default.
- W2898890640 title "ROS-independent inhibition of melanoma tumor growth by luteolin involves BRAF and the MAPK pathway" @default.
- W2898890640 doi "https://doi.org/10.1016/j.freeradbiomed.2018.10.148" @default.
- W2898890640 hasPublicationYear "2018" @default.
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