Abstract
Abstract Aims Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. Polydatin is a nutraceutical agent derived from trans-resveratrol with established anti-inflammatory and anti-atherogenic properties. We aimed to assess whether palmitoylethanolamide combined to polydatin, co-incubated during doxorubicin and trastuzumab, reduces anticancer drugs-related cardiotoxicity in cellular models. Methods Human vascular endothelial cells were exposed to subclinical concentration of doxorubicin (at 100 and 200 nM) combined to trastuzumab (at 100 and 200 nM) alone or in combination with a formulation composed by palmitoylethanolamide and polydatin (500 nM and 50 µM, respectively) for 48 h. 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 peroxisome proliferator-activated receptor-α; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results Palmitoylethanolamide combined to polydatin co-incubated with doxorubicin exerts vasculoprotective effects, enhancing cell viability of 54.7–68.3% compared to untreated cells (P < 0.001 for all). The formulation reduced significantly the cardiotoxicity through peroxisome proliferator-activated receptor-α–related pathways and NLRP3 inflammasome but without the involvement of calcium homeostasis. Conclusion The present study demonstrates that palmitoylethanolamide and polydatin protects against vasculotoxicity of doxorubicin and trastuzumab by promoting an anti-inflammatory phenotype, representing a new therapeutic approach to resolve doxorubicin-induced vasculotoxicity and inflammation.
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