Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E, Lisboa, Portugal; Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E, Lisboa, Portugal; Universidad de Salamanca-IBSAL-Hospital Universitario, Servicio de Hematología, Salamanca, Spain.
Exp Hematol. 2019 Apr;72:60-71.e11. doi: 10.1016/j.exphem.2019.02.002. Epub 2019 Feb 13.
BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by JAK-STAT pathway activation, but epigenetic alterations also play an important pathophysiological role. These can be pharmacologically manipulated with histone deacetylase inhibitors (HDACIs), which have proven to be clinically effective in the treatment of MPNs but exhibit dose-limiting toxicity. The treatment of primary MPN cells with vorinostat modulates the expression of genes associated with apoptosis, cell cycle, inflammation, and signaling. The induction of this transcriptional program results in decreased cellular viability, paralleled by a decrease in levels of reactive oxygen species (ROS). In vitro manipulation of ROS levels revealed that the reduction of ROS levels promoted apoptosis. When vorinostat was combined with antioxidant agents, the apoptosis of MPN cells increased in a synergistic manner. The results described here suggest a novel and promising therapeutic strategy combining HDACIs with ROS-reducing agents to treat MPNs.
BCR-ABL 阴性骨髓增殖性肿瘤（MPN）由 JAK-STAT 通路激活驱动，但表观遗传改变也在重要的病理生理学中发挥作用。这些可以通过组蛋白去乙酰化酶抑制剂（HDACI）进行药理学操作，在 MPN 的治疗中已被证明具有临床疗效，但存在剂量限制毒性。伏立诺他处理原发性 MPN 细胞可调节与凋亡、细胞周期、炎症和信号传导相关的基因表达。这种转录程序的诱导导致细胞活力降低，同时活性氧（ROS）水平降低。体外 ROS 水平的操作表明，降低 ROS 水平可促进细胞凋亡。当伏立诺他与抗氧化剂联合使用时，MPN 细胞的凋亡呈协同增加。这里描述的结果表明，联合使用 HDACI 和降低 ROS 的药物是一种治疗 MPN 的新型有前途的治疗策略。
