Abstract 9383: Dapagliflozin, an Sglt2 Inhibitor, Reduces Expression of Myd88, Nlrp3 and Nf-kb During Exposure to Doxorubicin and Trastuzumab in Cellular Models

Abstract

Introduction: The cumulative incidence of cardiac events in women treated with anthracycline and trastuzumab at 1 year after the diagnosis of breast cancer was 16.4%, at 2 years 23.8 %, and at 3 years 28.2%. Sodium glucose cotransporter 2 inhibitors, reduces HF hospitalization and cardiovascular mortality. Hypothesis: We hypothesize that dapagliflozin could exerts cardioprotective effects in cellular models of doxorubicin and trastuzumab-induced cardiotoxicity Methods: Human cardiomyocytes (HL-1 cells) were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin at 50 nM for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde, 4-hydroxynonenal and intracellular Ca 2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3 inflammasome, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF were also performed. Results: Dapagliflozin increased cell viability during exposure to doxorubicin and trastuzumab. Dapagliflozin reduces intracellular Ca 2+ overload ( -47,6% vs cells treated only to anticancer drugs; p<0,001), lipid peroxidation (mean reduction of 35-43 % compared to cells exposed only to anticancer drugs; p<0,001). The expression of Myd88, NLRP3 and NF-kB was significantly reduced after treatment with dapagliflozin (-37,5, -28 and -37 % vs cells exposed only to anticancer drugs, respectively; p<0.001). A specific set of cytokines, such as IL-1α, IL-1β, IL-6, IL17-α, TNF-α and IL-18 were significantly reduced after treatment with dapagliflozin indicating its anti-inflammatory, anti-fibrotic and cytoprotective properties which could prevent arrhythmic and myocardial events. Conclusions: Dapagliflozin exerts significant cardioprotective properties mediated by iCa 2+ content that consequently reduces peroxidation and NLRP3- Myd88 expression; inhibition of NLRP3 inflammasome by dapagliflozin decreased the expression of cytokines involved in cardiotoxicity.