机构地区:[1]Department of Biology,E.and E.S.(DiBEST),Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory,University of Calabria,Cosenza,Italy [2]Department of Pharmacy,Health and Nutritional Sciences,University of Calabria,Cosenza,Italy [3]Department of Biology,E.and E.S.(DiBEST),University of Calabria,Rende,Italy [4]Department of Biology,E.and E.S.(DiBEST),Organ and System Physiology Laboratory,University of Calabria,Cosenza,Italy [5]Department of Biology,E.and E.S.(DiBEST),Unit of Biochemistry,Molecular Biotechnology,and Molecular Biology,University of Calabria,Cosenza,Italy [6]CNR Institute of Biomembranes,Bioenergetics and Molecular Biotechnology,Bari,Italy [7]BIOVIIIX,Napoli,Italy [8]National Institute of Cardiovascular Research(INRC),Bologna,Italy
出 处:《Acta Pharmacologica Sinica》2025年第3期618-631,共14页中国药理学报(英文版)
基 金:supported by“SI.F.I.PA.CRO.DE.–Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE”(PON ARS01_00568).
摘 要:Fragment crystallizable gamma receptors(FcγRs)mediate various cellular responses with significant cardiovascular implications.They contribute to the anticancer activity of trastuzumab(TRZ),a recombinant humanized monoclonal antibody that interferes with human epidermal growth factor receptor 2(HER2),thereby blocking its physiological function in cardiac cells.This is responsible for cardiac complications that hamper TRZ clinical application.In this study we investigated the involvement of FcγRs in the TRZ cardiotoxicity.We used a recombinant antigen-binding fragment(Fab)of TRZ(rFab-HER2)to examine whether the absence of the Fc region resulted in fewer cardiomyocyte toxicity while preserving TRZ’s ability to inhibit HER2.When exposed to rFab-HER2,AC16 human adult ventricular cardiomyocytes were less vulnerable to damage and death,than to TRZ.Specifically,TRZ exhibited cytotoxicity at a lower concentration(150µg/mL,corresponding to~1µM)compared to rFab-HER2(250µg/mL,corresponding to~5µM).Like TRZ,rFab-HER2 negatively modulated HER2 levels in cardiomyocyte(without inducing cytotoxic activity in BJ human fibroblast cells that either did not express or express very low levels of HER2)and inhibited the downstream ERK/AKT cascades.But rFab-HER2 did not alter cardiomyocyte mitochondrial dynamic balance,and affect apoptosis and inflammation,while it limited cytosolic and mitochondrial ROS indicators.On contrary,the Fc region(50−250μg/mL)exerted direct cytotoxic action on cardiomyocytes(but not on human fibroblasts that lacked Fc receptors).TRZ(150μg/mL)markedly upregulated the expression level of FcγRIIA(a FcγRs strongly involved in TRZ-induced antibody-dependent cellular toxicity)in cardiomyocytes,whereas the Fab fragment(150μg/mL)had no effect.Our results demonstrate that Fc region plays an important pathogenic role in TRZ-induced cardiomyocyte toxicity.In addition,targeting FcγRIIA might contribute to the off-target effects of TRZ therapy.
关 键 词:cardiac complications TRASTUZUMAB rFab-HER2 Fc region FcyRIIA HER2
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