N-acyl phosphatidylethanolamine phospholipase D produces palmitoylethanolamide (PEA), an endogenous fatty acid mediator, from membrane phospholipids. It is a brand-new analgesic with anti-inflammatory properties via activating pathways connected to PPAR. For a study, researchers sought to determine if palmitoylethanolamide co-incubated with doxorubicin and trastuzumab reduced cardiotoxicity associated with anticancer medicines in cellular models.

Cardiomyocytes and human vascular endothelial cells were treated for 48 hours to subclinical concentrations of doxorubicin (at 100 and 200 nM) paired with trastuzumab (at 100 and 200 nM) alone or in conjunction with a formulation including palmitoylethanolamide (at 500 nM). Following the incubation time, they carried out the following tests: intracellular Ca2+ homeostasis, lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), and examination of mitochondrial dehydrogenase activity to determine cell survival. Additionally, pro-inflammatory studies were carried out (NLRP3 inflammasome activation, expression of peroxisome proliferator-activated receptor-α, mTORC1 Fox01/3a, p65/NF-κB, and release of cytokines implicated in cardiotoxicity (Interleukins 1β, 8, 6).

As palmitoylethanolamide and doxorubicin were combined, they have cardioprotective and vasculoprotective effects that increase cell viability by 56.3–78.7% compared to untreated cells (P<0,001 for all). Notably, PEA dramatically decreased the cardiotoxicity through NLRP3 inflammasome and peroxisome proliferator-activated receptor-related pathways, but not through affecting calcium homeostasis. Furthermore, its anti-inflammatory action was further supported by the reduced levels of many cytokines and chemokines.

The study demonstrated that palmitoylethanolamide protects against the vasculotoxicity and cardiotoxicity of trastuzumab and doxorubicin by promoting an anti-inflammatory phenotype, offering a novel therapeutic strategy to treat inflammation and vasculo-cardiotoxicity brought on by doxorubicin.

Reference: annalsofoncology.org/article/S0923-7534(22)01894-4/fulltext