Berberine associated to SGLT2i Dapagliflozin synergistically reduces cardiac cell apoptosis during exposure to Trastuzumab through reduction of AGEs and IL-6 and induction of pAMPK

Abstract Background Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction reduced ejection fraction or HF during treatment. Dapagliflozin is a SGLT2i cardio-renal benefits. In DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes Heart Failure) trial, sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased risk worsening events and cardiovascular death fraction. Berberine nutraceutical compound characterized by multiple metabolic effects with/without diseases. Recent preclinical systematic review indicated that significantly reduces myocardial infarct size incidence arrhythmia, improves cardiac function, ameliorates apoptosis. Purpose To investigate on potential cardioprotective properties associated to against HER-2 blocking agent-induced cardiotoxicity Methods Human fetal cardiomyocytes (HFC cell line) were exposed subclinical concentration trastuzumab (200 nM) alone co-incubated mM) (50 both combination for 48 h. After incubation period, we performed following tests: viability, apoptosis, expression NLRP3 inflammasome, methylglyoxal leukotrienes-B4. Expression pAMPK was analyzed through western blot. Moreover, quantification IL-6 ELISA method. Results increased viability Trastuzumab. When combined, synergistically cells (p<0.001 vs Trastuzumab). Cell apoptosis 32.5, 41.8 72.7% berberine, combined (vs group). Methylglyoxal,a marker AGEs, strongly compared untreated cells. Western blot analysis clearly demonstrate induced berberine Dapagliflozin, improving mitochondrial metabolism. No significant changes Leukotriene B4 seen. Intracellular levels 46.3, 62.7 86.3% Conclusion exerts HER2-bloking agent induces an anti-inflammatory phenotype reduction biomarkers involved heart failure Funding Acknowledgement Type funding sources: Public Institution(s). Main source(s): Ricerca Corrente, Ministero della Salute