Abstract 4222: N-acetyl-L-cysteine (NAC) sensitizes psammaplin A induced DNA damage in malignant hematologic cells by enhancing HDAC inhibition

Abstract Psammaplin A (PsA) is a symmetrical bromotyrosine-derived disulfide dimer isolated from the Psammaplysilla sponge. PsA is a selective natural Class I HDAC inhibitor, that requires reduction into monomer with glutathione (GSH). Cell growth inhibition and apoptosis was determined in 12 malignant hematologic cell lines revealed 8 lines sensitive (more than 50% inhibition at 1 μM) and 4 lines insensitive (less than 20% inhibition at 1 μM). PsA induces acetylation of H3 and DNA damage detected with γ-H2A.X in the sensitive lines, but not in the four insensitive cell lines. The sensitivity of PsA in these lines correlates with HDAC inhibition and reduced GSH levels. The insensitive cell lines have lower GSH levels without HDAC inhibition. N-acetyl-L-cysteine (NAC) acts as a precursor of GSH synthesis and is used as an antioxidant. Pretreatment with 5 mM NAC following by PsA enhances cell growth inhibition 10 fold. NAC plus PsA is more effective than the HDAC inhibitor SAHA, which is not enhanced by NAC, to inhibit cell growth in vitro. Western blot analysis shows that NAC sensitizes PsA effect by increasing HDAC inhibition as measured by acetylated H3 and by DNA damage marker γ-H2A.X with upregulation of GSH. Chemical studies reveal that GSH, but not NAC, reduces PsA into a monomer. PsA is enhanced by NAC to inhibit tumor growth in MOML13 xenograft models without causing toxicity. These data support that NAC enhances PsA effect by increasing intracellular GSH which reduces PsA into a HDAC inhibiting monomer with increased cancer cell growth inhibition. Citation Format: Yu Bao, Yumei He, Dan Liu, Ping Gong, Samuel Waxman, Yongkui Jing. N-acetyl-L-cysteine (NAC) sensitizes psammaplin A induced DNA damage in malignant hematologic cells by enhancing HDAC inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4222.