COTI-2 is a third-generation thiosemicarbazone, which is effective against a diverse group of human cancer cell lines at nanomolar concentrations. COTI-2 also showed superior activity against tumor cells, in vitro and in vivo. As a high efficacy and low toxicity agent, it currently candidates in a phase I clinical study of gynecological malignancies and head and neck squamous cell carcinoma (HNSCC). However, its effect in pediatric T-cell acute lymphoblastic leukemia (T-ALL) is not clear. This study investigates the effect of COTI-2 on T-ALL Jurkat cells in vitro and in vivo. Jurkat cells were exposure to COTI-2 at different concentration and time. Cell apoptosis was detected by flow cytometry to examine the sensitivity of Jurkat cell lines treated with either COTI-2 alone or in combination with MiR-203 mimic or inhibitor in vitro. An orthotopic mouse model was used to examine the sensitivity of Jurkat cells treated with COTI-2 in vivo. Western blotting and RT-qPCR were performed to dissect molecular mechanisms. The results showed that COTI-2 promotes apoptosis of Jurkat cells in dose-and time-dependent way. Enforced expression of miR-203 promotes COTI-2-mediated cell apoptosis, whereas miR-203 silencing attenuates COTI-2-mediated cell apoptosis in Jurkat cells in vitro. COTI-2 is also effective against growth of Jurkat cells in vivo. Mechanistically, COTI-2 induced miR-203 upregulation and inhibited caspase-3/9 activaty leading to inhibition of cell apoptosis. Taken together, COTI-2 inhibits tumor growth in vitro and in vivo in Jurkat cells likely through miR-203-dependent mechanisms. COTI-2 may be a potential approach for T-ALL treatment.

中文翻译：

---

COTI-2通过上调miR-203诱导小儿急性淋巴细胞白血病细胞凋亡。

COTI-2是第三代硫代半碳酰胺，对纳摩尔浓度的多种人类癌细胞系有效。COTI-2还显示出在体外和体内对肿瘤细胞的优异活性。作为一种高效，低毒的药物，它目前正在妇科恶性肿瘤和头颈部鳞状细胞癌（HNSCC）的I期临床研究中候选。然而，其在小儿T细胞急性淋巴细胞白血病（T-ALL）中的作用尚不清楚。这项研究调查了COTI-2在体外和体内对T-ALL Jurkat细胞的影响。Jurkat细胞以不同的浓度和时间暴露于COTI-2。通过流式细胞术检测细胞凋亡，以检查单独用COTI-2或与MiR-203模拟物或抑制剂联合使用的Jurkat细胞系的体外敏感性。原位小鼠模型用于检查体内用COTI-2处理的Jurkat细胞的敏感性。进行了蛋白质印迹和RT-qPCR解剖分子机制。结果表明，COTI-2以剂量和时间依赖性方式促进Jurkat细胞凋亡。增强表达的miR-203促进了COTI-2介导的细胞凋亡，而miR-203沉默则减弱了Jurkat细胞中COTI-2介导的细胞凋亡。COTI-2对体内Jurkat细胞的生长也有效。从机理上讲，COTI-2诱导了miR-203的上调并抑制了caspase-3 / 9的活化，从而导致细胞凋亡的抑制。综上所述，COTI-2可能通过miR-203依赖性机制在Jurkat细胞中体外和体内抑制肿瘤生长。COTI-2可能是T-ALL治疗的潜在方法。