Effects of SGLT2i dapagliflozin in primary prevention of cardiotoxicity induced by short-term anthracycline and HER2 blocking agent therapy through inhibition of MyD88 and NLRP-3 pathways.

Abstract

12023 Background: Anthracyclines, such as doxorubicin, and HER-2 blocking agents, like 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 agents-mediated cardiotoxicity in preclinical models. Methods: Female C57Bl/6 mice were treated for 10 days with a saline solution or DOXO-Trastuzumab (both at 2.17 mg/kg), DAPA (10 mg/kg), or DOXO-Trastuzumab combined with DAPA. Systemic levels of ferroptosis-related biomarkers, galectin-3, high-sensitivity C-reactive protein (hs-CRP), and pro-inflammatory chemokines (IL-1 α , 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. After treatments, immunohistochemical staining of myocardial and renal IL-1, IL6, CXCR4, NLRP-3 and Myd88 was performed. Results: DAPA prevented the reduction of radial and longitudinal strain and ejection fraction after 10 days of treatment with DOXO-Trastuzumab. A reduced myocardial expression of NLRP-3, MyD-88, IL-6 and IL1 was seen in the DOXO-TRA+ DAPA group compared to DOXO-TRA mice. Systemic levels of IL-1β, IL-6, TNF-α, G-CSF, and GM-CSF were significantly reduced after treatment with DAPA. Serum levels of galectine-3 and hs-CRP were strongly enhanced in the DOXO-Trastuzumab group; on the other hand, their expression was reduced in the DAPA+DOXO-Trastuzuab group. Troponin-T, B-type natriuretic peptide (BNP), and N-Terminal Pro-BNP (NT-pro-BNP) were strongly reduced in the DOXO-Trastuzumab+DAPA group, revealing cardioprotective properties of SGLT2i. Mice treated with DOXO-Trastuzumab and DAPA exhibited reduced myocardial and renal IL-1, IL6, CXCR4, NLRP-3 and Myd88 IHC straining. Conclusions: 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.