?Inhibition of of the Plasma membrane Ca2+-ATPase by Flavonoids

RINALDI, D.; MANGIALAVORI, I.C., ONTIVEROS, M., RIESCO, A., MARDER, M.; ROSSI, J.P. FERREIRA-GOMES MS

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Congreso; Latin American crosstalk in Biophisycs and physiology; 2015

Postlatam

Inhibition of the Plasma membrane Ca2+-ATPase by Flavonoids SBF.uy Rinaldi, D., Mangialavori, I.;Ontiveros, M.; Riesco, A., Marder, M.;Rossi, J.P.; Ferreira-Gomes, M.Instituto de Química y Fisicoquímica Biológicas. ?Prof.Paladini?.Departamento de Química Biológica, Facultad de Farmacia y Bioquímica. Universidad deBuenos Aires.Corresponding author: msferreiragomes@qb.ffyb.uba.arFlavonoids are commonly found infruit and vegetables. Some of flavonoids have been reported to reach levels asseveral micromolars in human blood plasma [1]. These compounds would have cancer chemoprotectiveproperties by triggering apoptosis via the Ca2+‑dependentmitochondrial pathway which can be activated through an elevation of cytosolic [Ca2+].Theincrease of cytosolic [Ca2+] could be due to the fact that someflavonoids are able to inhibit some Ca2+ removing systems, as  sarcoplasmic/endoplasmic reticulum Ca2+ATPase and plasma membrane calcium ATPase (PMCA) [2]. The purpose of the present work wasto investigate the effect of several flavonoids on PMCA and to establish a quantitativestructure-activity relationship. The experiments were performed with vesiclesand purified PMCA obtained from human erythrocytes. The chromone, chalcone, flavanone andflavone (structural cores of some flavonoids) did not inhibit to PMCA (relativeto the control at 100 mM). The inhibition wasfavorable for: (a) a double bond between carbons 2-3; (b) the flavone nucleus issubstituted with OH groups; (c) the presence of an OH group in the 4' position orin 3´ position. The presence of an OH group at the 3 position or thepresence of an O-glucose at the 8 position was not important for the inhibition.The glycosylation in the 7 or 3 position is not favorable for the inhibition.On the other hand, we investigated the mechanism of inhibition for those flavonoids that inhibited toPMCA in the micromolar concentration range. The compounds studied were: quercetin, epigallocatechin 3-gallate and gossypin. The results showed that (1) flavonoidsact as inhibitor in both vesicles and purified systems and (2) the inhibition was more potent in purified PMCA (<K0.5).These results suggest that PMCAcould be a specific target of flavonoids contributing to initiationof apoptosis in cancer cells.  [1] Erlund I, et al. Eur. J. Clin. Nutr. 56, 891?898, 2002.[2] OgunbayoOA and MichelangeliF. FEBSJ. 281, 766-777, 2014. With grants of ANPCYT, CONICET and UBACYT.