NLRP3/IL-1 pathway was reduced by semaglutide and dapagliflozin in association therapy under exposure to anthracyclines in hyperglycemic conditions

Abstract Background Hyperglycemia and advanced glycation end products (AGES) are key players of heart failure and atherosclerosis in patients with/without cancer through the stimulation of pro-inflammatory signaling. GLP-1 receptor agonists exerts cardiorenal benefits in patients with/without diabetes, proposing themselves as a new cardioprotective strategy in a broad patient setting, including patients with T2DM. Dapagliflozin have beneficial cardiorenal properties, including the improvement of systolic and diastolic functions, increases in calcium homeostasis, reduction of afterload and oxidative stress, improvement of mitochondrial functions in cardiomyocytes. Cancer patients with hyperglycemia are exposed to very high risk of heart failure and need new pharmacological strategies to reduce the magnitude of CTRCD. Purpose We report for the first time the results of the use of combination therapy with a glucagon-like peptide-1 receptor agonist and Dapagliflozin for the primary prevention of anthracyline-mediated cardiotoxicity under hyperglycemia. Methods Human cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin, (200 nM), alone or in combination with dapagliflozin (50 nM) and/or semaglutide (100 nM) for 48h under hyperglycemia (25mM). After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and expression of cytokines involved in cardiotoxicity (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IFN-γ, TNF-α, G-CSF, GM-CSF). Results Dapagliflozin and semaglutide co-incubated with doxorubicin exerts synergistic and significant cardioprotective effects, compared to monotherapy regimens, enhancing cell viability of 87.9-94.2 % compared to only DOXO treated cells under high glucose (p0,001 for all). Significant reductions of oxidative stress, ferroptosis and intracellular levels of NLRP-3, MyD88, p65NF-KB, IL-1α, IL-1β, IL-6, IL-12, IL17-α, TNF-α, G-CSF were seen in semaglutide/dapagliflozin group vs only DOXO groups under hyperglycemia (p0.01). Conclusion For the first time, Combination Therapy With Semaglutide and Dapagliflozin exerts synergistic anti-inflammatory effects to reduce anthracycline-mediated cardiotoxicity through NLRP-3, Myd-88 and . The overall picture of the study warrent on the use of semaglutide and dapagliflozin in primary prevention of CTRCD in cancer patients with hyperglycemia.