Abstract
Abstract Background The use of anthracyclines as a standard cancer therapy is limited by the potential for the development of cardiac dysfunction, arrhythmias, and clinical heart failure. The incidence of cardiac dysfunction or heart failure post-trastuzumab plus anthracycline therapy is higher compared to monotherapy regimen, exposing cancer patients to cardiotoxic risk. Dapagliflozin exerts several cardiometabolic benefits in patients with and wthout T2DM through SGLT2-NLRP3 mediated pathways. In this study, we highlighted on new beneficial properties of Dapagliflozin in preclinical models of doxorubicin-HER-2 blocking agent induced cardiotoxicity. Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg associated to HER-2 blocking agent i.p at 2,25 mg/kg (DOXO/TRA, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin-HER-2 blocking agent combined to DAPA (DOXO/TRA–DAPA, n=6). Cardiac function studies, including EF, FS and radial/longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100) . Systemic levels of ferroptosis-related biomarkers, galectin-3, high-sensitivity C-reactive protein (hs-CRP), and pro-inflammatory 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. Results Dapagliflozin increased EF and FS compared to DOXO groups (p < 0.01), prevented the reduction of radial and longitudinal strain after 10 days of treatment with DOXO-TRA (RS) 40.2% in EMPA-DOXO vs 14.9% in DOXO-TRA mice; LS – 26,8 % in DOXO/TRA-DAPA vs – 9,7.3% in DOXO/TRA mice (p < 0.001 for both). Dapagliflozin associated to Doxorubicin reduces of 53,8 % plasma levels of H-FABP compared to DOXO group (p<0.001). Myocardial expression of H-FABP were also reduced, indicating cardioprotective properties of SGLT2i. Significant reductions in ferroptosis, xanthine oxidase expression, cardiac fibrosis and apoptosis in DAPA associated to DOXO/TRA were also seen. A reduced expression of systemic pro-inflammatory cytokines and NLRP3 was also seen in in DOXO/TRA-DAPA group compared to DOXO/TRA (p < 0.001). Conclusion For the first time, Dapagliflozin demonstrated significant improvements in cardiac functions and reductions of systemic H-FABP and troponin levels during doxorubicin associated to HER- blocking agent therapy, indicating new potential pathways of cardioprotection in cancer patients.
Published Version
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