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.
Year: 2025
Type: conference-abstract
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.
Source: Journal of Clinical Oncology
Authors: Vincenzo Quagliariello, Annabella Di Mauro, Gerardo Ferrara, Francesca Bruzzese, Giuseppe Palma, Antonio Luciano, Maria Laura Canale, Irma Bisceglia, Martina Iovine, Marino Scherillo, Fabrizio Maurea, Alessandro Inno, Matteo Barbato, Massimiliano Berretta, Alfredo Mauriello, Michelino De Laurentiis, Nicola Maurea
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4410816165