LAUSR

e15065 Background: : Polydatin has anticancer and anti-inflammatory properties, however no studies investigated on its putative cardioprotective effects against anticancer therapies. Sunitinib, a recently-approved, multi-targeted tyrosine kinases inhibitor, prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. We investigated on the reduction of cytokines and growth factors of polydatin resulting in putative cardioprotective effects. Methods: Human fetal cardiomyocytes were untreated (control) or treated for 48 h with polydatin (50,100,200 and 400 µM) or sunitinib (5,10,25 and 50 µM) alone or combined to polydatin. 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 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Exposure of adult cardiomyocytes to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly intracellular reactive oxygen species, lipid peroxidation and cytochrome c release from mitochondria leading to a reduction in cell death compared to cells exposed to sunitinib alone. Polydatin reduces expression of pro-inflammatory cytokines and growth factors involved in myocardial damages and down-regulates the signaling pathway of NLRP3 inflammasome and NF-κB, increasing cellular resistance to sunitinib-mediated damages. Conclusions: Data of the present study, although in vitro, indicate that polydatin, besides reducing oxidative stress, has cardioprotective and anti-inflammatory properties, thus indicating one the mechanism(s) by which this metabolite of resveratrol might decrease sunitinib-mediated cardiotoxicity.