Truong Nhu, Goodis Christopher C, Cottingham Andrea L, Shaw Jacob R, Fletcher Steven, Pearson Ryan M
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States.
Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.
ACS Pharmacol Transl Sci. 2022 Oct 10;5(11):1128-1141. doi: 10.1021/acsptsci.2c00119. eCollection 2022 Nov 11.
Histone deacetylase inhibitors (HDACi) induce potent anti-inflammatory responses when used to treat inflammatory diseases. Suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, decreases pro-inflammatory cytokine levels and attenuates cytokine storm in sepsis; however, its toxicity profile toward immune cells has limited its use as a sepsis therapeutic. Here, we developed a modification to SAHA by -hydroxymethylating the capping group to generate SAHA-OH. We discovered that SAHA-OH provides a favorable improvement to the toxicity profile compared to SAHA. SAHA-OH significantly reduced primary macrophage apoptosis and splenic B cell death as well as mitigated organ damage using a lipopolysaccharide (LPS)-induced endotoxemia mouse model. Furthermore, SAHA-OH retained anti-inflammatory responses similar to SAHA as measured by reductions in LPS-induced proinflammatory cytokine secretions in vitro and in vivo. These effects were attributed to a decreased selectivity of HDAC1, 2, 3, 8 and an increased selectivity for HDAC6 for SAHA-OH as determined by IC values. Our results support the potential for SAHA-OH to modulate acute proinflammatory responses while mitigating SAHA-associated drug toxicity for use in the treatment of inflammation-associated diseases and conditions.
组蛋白去乙酰化酶抑制剂（HDACi）在用于治疗炎症性疾病时可诱导强烈的抗炎反应。泛HDACi伏立诺他（SAHA）可降低促炎细胞因子水平，并减轻脓毒症中的细胞因子风暴；然而，其对免疫细胞的毒性限制了它作为脓毒症治疗药物的应用。在此，我们通过将封端基团进行羟甲基化修饰开发了一种SAHA的变体，即SAHA-OH。我们发现，与SAHA相比，SAHA-OH的毒性有了明显改善。使用脂多糖（LPS）诱导的内毒素血症小鼠模型，SAHA-OH显著减少了原代巨噬细胞凋亡和脾脏B细胞死亡，并减轻了器官损伤。此外，通过体外和体内LPS诱导的促炎细胞因子分泌减少来衡量，SAHA-OH保留了与SAHA相似的抗炎反应。这些作用归因于根据IC值测定，SAHA-OH对HDAC1、2、3、8的选择性降低，而对HDAC6的选择性增加。我们的结果支持了SAHA-OH在减轻SAHA相关药物毒性的同时调节急性促炎反应的潜力，可用于治疗炎症相关疾病和病症。
