Oxidative DNA double strand breaks and autophagy in the antitumor effect of sterically hindered platinum(II) complexes in NSCLCs.
Oxidative DNA double strand breaks and autophagy in the antitumor effect of sterically hindered platinum(II) complexes in NSCLCs.
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DOI：
10.18632/oncotarget.15944
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发表时间：
2017-05-09
期刊：
影响因子：
--
通讯作者：
Gou S
中科院分区：
文献类型：
--
作者：
Chen F;Wang X;Jin X;Zhao J;Gou S
以（1 R，2 R）-N1，N2-二异丁基-1，2-环己二胺为载体配体，以N1，N2-二异丁基为位阻，设计、合成并表征了一系列新型铂（II）配合物。体外生物活性测试表明，与单取代配合物3a相比，配合物3对肺癌细胞，尤其是非小细胞肺癌（NSCLC）的细胞毒活性有所提高，表明烷基位阻对其抗肿瘤活性有显著影响。然而，其机制仍不清楚。进一步的研究表明，复合物3可诱导细胞内ROS的过度产生，DNA双链断裂，抑制细胞核内DNA损伤修复蛋白的激活，导致细胞周期阻滞和细胞死亡。此外，复合物3可通过自噬空泡的积累和自噬蛋白表达的改变来诱导自噬。有趣的是，活性氧清除剂N-乙酰半胱氨酸（NAC）能更显著地逆转复合物3诱导的DNA双链断裂和自噬反应。结果表明，活性氧的产生在N1，N2-二异丁基配合物3的抗肿瘤作用中起着重要作用，在DNA双链断裂和自噬反应中起着重要作用。我们的研究提供了一种新的治疗策略，并为N1，N2-二异丁基作为空间位阻的配合物的抗癌研究提供了新的见解。
A series of novel platinum(II) complexes with (1R,2R)-N1,N2-diisobutyl-1,2-diaminocyclohexane as a carrier ligand, while N1,N2-diisobutyl moiety serving as steric hindrance were designed, synthesized and characterized. The in vitro biological assays demonstrated that complex 3 had increased cytotoxicity against lung cancer cells, especially non-small-cell lung cancer (NSCLC) compared to its mono-substituted complex 3a, indicating that the sterically hindered alkyl moieties have significant influences on its antitumor property. However, the mechanism still remains unclear. The further studies revealed that complex 3 could induce ROS overproduction, severe DNA double strands breaks and inhibit the activation of DNA damage repair proteins within nucleus, leading to cell-cycle arrest and cell death. Moreover, complex 3 could induce autophagy via the accumulation of autophagic vacuoles and alterations of autophagic protein expression. Interestingly, the ROS scavengers, N-acetyl-cysteine (NAC) could reverse complex 3-induced DNA double strands breaks and autophagic responses more significantly compared to complex 3a. The results demonstrated that the ROS generation plays an important role in the DNA double strands breaks and autophagic responses in the antitumor effect of complex 3 with N1,N2-diisobutyl moiety. Our study offered a novel therapeutic strategy and put new insights into the anticancer research of the complexes with N1,N2-diisobutyl moiety served as steric hindrance.