A cisplatin-based platinum(IV) prodrug containing a glutathione s-transferase inhibitor to reverse cisplatin-resistance in non-small cell lung cancer
A cisplatin-based platinum(IV) prodrug containing a glutathione s-transferase inhibitor to reverse cisplatin-resistance in non-small cell lung cancer
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一种基于顺铂的铂 (IV) 前药，含有谷胱甘肽 S-转移酶抑制剂，可逆转非小细胞肺癌的顺铂耐药性
DOI：
10.1016/j.jinorgbio.2019.01.014
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发表时间：
2019-04-01
影响因子：
3.9
通讯作者：
Gou, Shaohua
中科院分区：
文献类型：
--
作者：
Chen, Hong;Wang, Xinyi;Gou, Shaohua
设计并研究了含有谷胱甘肽 s-转移酶 (GST) 抑制剂 6-(7-硝基-2,1,3-苯并恶二唑-4-基硫基)己醇 (NBDHEX) 的顺铂 Pt(IV) 前药复合物 1，旨在通过抑制癌细胞中过度表达的 GST 来克服顺铂耐药性并降低其毒性。在抗坏血酸存在下，该络合物可以被还原以释放其活性 Pt(II) 物质和轴向配体。在细胞毒性研究中，复合物1对所有测试的癌细胞，特别是对顺铂耐药的A549/DDP细胞，显示出比顺铂和NBDHEX更有效的抗癌活性，其耐药因子值为0.37。通过有效抑制 GST，发现与顺铂相比，复合物 1 能够促进 A549 细胞和 A549/DDP 细胞中更高的铂摄取并造成更严重的 DNA 损伤。进一步的机制研究表明它可以通过凋亡途径引发细胞死亡。 A549异种移植瘤小鼠模型的体内试验表明，复合物1比顺铂具有更高的抑瘤率和更低的毒性。总之，Pt(IV) 前药有潜力被开发为抗癌剂。
A Pt(IV) prodrug of cisplatin containing a glutathione s-transferase (GSTs) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), complex 1, was designed and studied aiming to overcome cisplatin-resistance and reduce its toxicity by inhibiting GSTs overexpressed in cancer cells. The complex could be reduced to release its active Pt(II) species and axial ligand in the presence of ascorbic acid. In cytotoxicity study, complex 1 showed more potent anticancer activity than cisplatin and NBDHEX against all the tested cancer cells, especially toward cisplatin resistant A549/DDP cells with a resistance factor value of 0.37. By effectively inhibiting GSTs, complex 1 was found to be able to promote higher platinum uptake and cause more severe DNA damage in both A549 cells and A549/DDP cells as compared with cisplatin. Further mechanism study indicated that it could trigger cell death via an apoptotic pathway. In vivo tests on A549 xenograft tumor mice model showed that complex 1 presented higher tumor inhibiting rate and lower toxicity than cisplatin as well. In all, the Pt(IV) prodrug has potential to be developed as an anticancer agent.