MyD-88/NLRP-3 inhibition by dapagliflozin protects against anthracycline and trastuzumab cardiotoxicity in preclinical models

Background Anthracyclines, such as doxorubicin, and HER-2 blocking agents, including trastuzumab, are integral in breast cancer treatment but are associated with significant cardiotoxicity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been suggested to provide cardio-renal benefits in the context of anthracycline therapy. However, the cardioprotective effects of SGLT2 inhibitors during combined anthracycline and HER-2 blocking agent therapy remain largely unexplored. The study aimed to investigate the cardioprotective potential of Dapagliflozin in primary prevention of anthracyclines and HER-2 blocking agent-induced cardiotoxicity in preclinical models. Methods Female C57Bl/6 mice were treated for 10 days with a saline solution (Sham) or Doxorubicin associated to HER-2blocking agent (both at 2.17 mg/kg in sequential therapy), Dapagliflozin (10 mg/kg), or Doxorubicin associated to HER-2 blocking agent combined with DAPA. Cardiac function were analyzed through VEVO 2100 (Fujifilm) .Myocardial expression of NLRP-3, MyD-88, CXCR4, H-FABP, Troponin-T and several chemokines (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 quantified through ELISA and IHC methods. Systemic levels of lipid peroxidation, cardiotoxicity biomarkers, including Mitofusin-2, Cardiac myosin light chain and growth differentiation factor type 15, were studied. Results Dapagliflozin prevents significantly EF and radial/longitudinal strain reduction in models of doxorubicin combined with HER-2 blocking agent (p<0.001). Additionally, myocardial NLRP-3, MyD-88, CXCR4, H-FABP, IL-1β and Troponin-T were significantly reduced compared to doxorubicin-HER2 mAb group, indicating anti-inflammatory and cardioprotective properties of dapagliflozin. Lipid peroxidation biomarkers and chemokines were significantly changed after dapagliflozin therapy. Serum levels of H-FABP, Troponin-T, BNP and hs-CRP were strongly reduced after dapagliflozin therapy, indicating systemic anti-inflammatory properties. Conclusion This study presents the first evidence of Dapagliflozin’s cardioprotective and anti-inflammatory effects in the context of anthracycline and HER-2 blocking agent-induced cardiotoxicity. These findings support the potential use of Dapagliflozin for primary prevention of cardiovascular events associated with doxorubicin-trastuzumab therapy in breast cancer patients, warranting further clinical investigation