Novel Triapine Derivative Induces Copper-Dependent Cell Death in Hematopoietic Cancers
Novel Triapine Derivative Induces Copper-Dependent Cell Death in Hematopoietic Cancers
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新型三硫平衍生物在造血系统癌症中诱导铜依赖性细胞死亡
DOI：
10.1021/acs.jmedchem.8b01996
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发表时间：
2019-03-28
影响因子：
7.3
通讯作者：
Zhu, Jidong
中科院分区：
文献类型：
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作者：
Chen, Ge;Niu, Chunyi;Zhu, Jidong
Trilidine是一种抑制核糖核苷酸还原酶的铁螯合剂，已在癌症治疗的临床试验中进行了评估。Trilazone与其他化疗药物联合治疗在某些血液恶性肿瘤中显示出有希望的疗效;然而，它对许多晚期实体瘤的疗效较差，可能是由于效力和药代动力学特性不令人满意。在本报告中，我们开发了一种具有有效抗肿瘤活性的三嗪衍生物IC 2S（10）。10 Preventive通过诱导线粒体活性氧产生和线粒体功能障碍来抑制造血系统癌症的增殖。与三氟甲磺酸不同，10以铜依赖性方式执行细胞毒性作用。硫氧还蛋白相互作用蛋白的诱导的上调表达导致硫氧还蛋白活性降低，从而允许c-Jun N-末端激酶和p38活化，并最终导致细胞死亡程序的执行。值得注意的是，10在小鼠异种移植模型中显示出良好的生物利用度和抑制肿瘤生长。综上所述，我们的研究将化合物10鉴定为铜依赖性抗肿瘤剂，其可用于治疗造血系统癌症。
Triapine, an iron chelator that inhibits ribonucleotide reductase, has been evaluated in clinical trials for cancer treatment. Triapine in combination with other chemotherapeutic agents shows promising efficacy in certain hematologic malignancies; however, it is less effective against many advanced solid tumors, probably due to the unsatisfactory potency and pharmacokinetic properties. In this report, we developed a triapine derivative IC2S (10) with potent antitumor activity. 10 Preferentially inhibited the proliferation of hematopoietic cancers by inducing mitochondria reactive oxygen species production and mitochondrial dysfunction. Unlike triapine, 10 executed cytotoxic action in a copper-dependent manner. 10 Induced up-expression of thioredoxin-interacting protein resulted in decreased thioredoxin activity to permit c-Jun N-terminal kinase and p38 activation and ultimately led to the execution of the cell death program. Remarkedly, 10 showed good bioavailability and inhibited tumor growth in mouse xenograft models. Taken together, our study identifies compound 10 as a copper-dependent antitumor agent, which may be applied to the treatment of hematopoietic cancers.