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Citarinostat and Momelotinib co-target HDAC6 and JAK2/STAT3 in lymphoid malignant cell lines: a potential new therapeutic combination.
Apoptosis ( IF 7.2 ) Pub Date : 2020-05-11 , DOI: 10.1007/s10495-020-01607-3
Maria Cosenza 1 , Monica Civallero 2 , Luigi Marcheselli 3 , Stefano Sacchi 1 , Samantha Pozzi 1
Affiliation  

Histone deacetylase (HDAC) inhibitors represent an encouraging class of antitumor drugs. HDAC inhibitors induce a series of molecular and biological responses and minimal toxicity to normal cells. Citarinostat (Acy-241) is a second generation, orally administered, HDAC6-selective inhibitor. Momelotinib (CYT387) is an orally administered inhibitor of Janus kinase/signal transducer of transcription-3 (JAK/STAT3) signaling. Momelotinib showed efficacy in patients with myelofibrosis. We hypothesized that both HDAC and JAK/STAT pathways were important in lymphoproliferative disorders, and that inhibiting JAK/STAT3 and HDAC simultaneously might enhance the efficacy of momelotinib and citarinostat without increasing toxicity. Accordingly, we tested the citarinostat + momelotinib combination in lymphoid cell lines. Citarinostat + momelotinib showed strong cytotoxicity; it significantly reduced mitochondrial membrane potential, down-regulated Bcl-2 and Bcl-xL, and activated caspases 9 and 3. Caspase-8 was upregulated in only two lymphoid cell lines, which indicated activation of the extrinsic apoptotic pathway. We identified a lymphoid cell line that was only slightly sensitive to the combination treatment. We knocked down thioredoxin expression by transfecting with small interfering RNA that targeted thioredoxin. This knockdown increased cell sensitivity to the combination-induced cell death. The combination treatment reduced Bcl-2 expression, activated caspase 3, and significantly inhibited cell viability and clonogenic survival.

中文翻译:

Citarinostat和Momelotinib在淋巴样恶性细胞系中共同靶向HDAC6和JAK2 / STAT3:一种潜在的新治疗组合。

组蛋白脱乙酰基酶(HDAC)抑制剂代表了令人鼓舞的一类抗肿瘤药物。HDAC抑制剂可诱导一系列分子和生物学反应,并且对正常细胞的毒性最小。Citarinostat(Acy-241)是第二代口服HDAC6选择性抑制剂。Momelotinib(CYT387)是口服的Janus激酶/转录3信号转导子(JAK / STAT3)信号传导抑制剂。莫洛替尼对骨髓纤维化患者显示出疗效。我们假设HDAC和JAK / STAT通路在淋巴增生性疾病中都很重要,并且同时抑制JAK / STAT3和HDAC可能会增强莫米替尼和citarinostat的疗效而不会增加毒性。因此,我们在淋巴样细胞系中测试了citarinostat + momelotinib的组合。Citarinostat +莫洛替尼显示出强烈的细胞毒性。它显着降低了线粒体膜电位,下调了Bcl-2和Bcl-xL,并激活了胱天蛋白酶9和3。Caspase-8仅在两种淋巴样细胞系中被上调,表明外在凋亡途径的激活。我们鉴定了对联合治疗仅稍敏感的淋巴样细胞系。我们通过靶向硫氧还蛋白的小分子干扰RNA转染了硫氧还蛋白的表达。这种击倒增加了细胞对组合诱导的细胞死亡的敏感性。联合治疗降低了Bcl-2的表达,激活了caspase 3,并显着抑制了细胞活力和克隆形成存活。并激活了胱天蛋白酶9和3。胱天蛋白酶8仅在两种淋巴样细胞系中被上调,这表明外在凋亡途径的激活。我们鉴定了对联合治疗仅稍敏感的淋巴样细胞系。我们通过靶向硫氧还蛋白的小分子干扰RNA转染了硫氧还蛋白的表达。这种击倒增加了细胞对组合诱导的细胞死亡的敏感性。联合治疗降低了Bcl-2的表达,激活了caspase 3,并显着抑制了细胞活力和克隆形成存活。并激活了胱天蛋白酶9和3。胱天蛋白酶8仅在两种淋巴样细胞系中被上调,这表明外在凋亡途径的激活。我们鉴定了对联合治疗仅稍敏感的淋巴样细胞系。我们通过靶向硫氧还蛋白的小分子干扰RNA转染了硫氧还蛋白的表达。这种击倒增加了细胞对组合诱导的细胞死亡的敏感性。联合治疗降低了Bcl-2的表达,激活了caspase 3,并显着抑制了细胞活力和克隆形成存活。我们通过靶向硫氧还蛋白的小分子干扰RNA转染了硫氧还蛋白的表达。这种击倒增加了细胞对组合诱导的细胞死亡的敏感性。联合治疗降低了Bcl-2的表达,激活了caspase 3,并显着抑制了细胞活力和克隆形成存活。我们通过靶向硫氧还蛋白的小分子干扰RNA转染了硫氧还蛋白的表达。这种击倒增加了细胞对组合诱导的细胞死亡的敏感性。联合治疗降低了Bcl-2的表达,激活了caspase 3,并显着抑制了细胞活力和克隆形成存活。
更新日期:2020-05-11
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