3′-Hydroxy-3,4′-dimethoxyflavone-induced cell death in human leukaemia cells is dependent on caspases and reactive oxygen species and attenuated by the inhibition of JNK/SAPK
2018
Estévez-Sarmiento, Francisco | Hernández, Elisa | Brouard, Ignacio | León, Francisco | García, Celina | Quintana, José | Estévez, Francisco | Ministerio de Economía y Competitividad (España) | European Commission
Flavonoids are phenolic substances that appear to exert beneficial effects in several chronic diseases, including cancer. Structure-activity relationships of the cytotoxic activity of a series of flavonols and their 3-methyl ether derivatives established that 3′-hydroxy-3,4′-dimethoxyflavone (flavonoid 11) displayed strong cytotoxicity against human leukaemia cell lines (HL-60, U-937 and MOLT-3), and cells that over-express the anti-apoptotic proteins, Bcl-2 and Bcl-x, and against P-glycoprotein-overexpressing K-562/ADR cells. This compound induced G-M cell cycle arrest and it was a potent apoptotic inducer on HL-60, MOLT-3, U-937 and U-937/Bcl-2 cell lines. Cell death was (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by a selective caspase-9 inhibitor, (ii) associated with cytochrome c release, the dissipation of the inner mitochondrial membrane potential (ΔΨ) and the activation of the mitogen-activated protein kinase pathway and (iii) partially blocked by the inhibition of c-jun NH terminal kinases/stress activated protein kinases (JNK/SAPK) signalling and by the free-radical scavenger N-acetyl-L-cysteine.
Show more [+] Less [-]This research was supported in part by the Spanish Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (CTQ2014-56362-C2-1-P and CTQ2015-63894-P).
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