Anacardic acid, a histone acetyltransferase inhibitor, stimulates hemolysis and eryptosis through energy depletion and calcium accumulation
TL;DR
This study presents a preclinical safety assessment of the HAT inhibitor anacardic acid (AA) in erythrocytes, given that anaemia is a clinically significant complication of chemotherapy.
Abstract
Abstract Histone acetyltransferase (HAT) inhibitors are promising epigenetic anticancer therapeutics. However, challenges remain regarding tissue specificity and off-target toxicity. This study presents a preclinical safety assessment of the HAT inhibitor anacardic acid (AA) in erythrocytes, given that anaemia is a clinically significant complication of chemotherapy. Freshly isolated erythrocytes were cultured in vitro with and without 1–10 µmol L–1 of AA, then markers and mechanisms of cell death were examined by fluorescence-activated cell sorting, spectrophotometry, and potentiometry. AA treatment induced marked hemolysis independently of oxidative stress, which was paralleled by Ca2+ accumulation and phosphatidylserine (PS) trans location. Morphological abnormalities were also observed upon AA treatment, including eryptotic loss of volume and elliptocyte phenotype. Co-treatment of AA with ATP, acetylsalicylic acid, NSC23766, or polyethylene glycol conferred significant cytoprotective effects. AA is cytotoxic to erythrocytes, causing both hemolysis and eryptosis, through non-genomic mechanisms involving Ca2+ signalling, metabolic exhaustion, K+ depletion, shrinkage and elliptocytic morphological aberrations. This toxic effect is sensitive to cyclooxygenase and Rac1 GTPase inhibition.