New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status.
New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status.
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DOI：
10.18632/oncotarget.13448
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发表时间：
2017-01-03
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影响因子：
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通讯作者：
Isab AA
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作者：
Altaf M;Monim-Ul-Mehboob M;Kawde AN;Corona G;Larcher R;Ogasawara M;Casagrande N;Celegato M;Borghese C;Siddik ZH;Aldinucci D;Isab AA
我们合成了九个新的联吡啶金(III)二硫代氨基甲酸酯配合物，并在一组癌细胞系中进行了表征和测试。体外研究表明，化合物1、2、4、5、7和8对前列腺癌、乳腺癌细胞、卵巢癌细胞和霍奇金淋巴瘤细胞的细胞毒性最强，其IC50值低于参比药物顺铂。活性最强的化合物1对卵巢癌细胞(A2780cis和2780cp-16)和乳腺癌顺铂耐药细胞的活性高于顺铂。化合物1确定了细胞氧化还原动态平衡的改变，导致ROS水平升高，线粒体膜电位降低，细胞色素c从线粒体释放，并激活caspase9和3。ROS清除剂NAC抑制ROS的产生，使细胞免于损伤。化合物1在肿瘤细胞中的活性高于对正常人间充质基质细胞的活性。金化合物的活性不依赖于P53的状态：对一组具有不同P53状态的非小细胞肺癌细胞株以及在P53基因被敲除的卵巢A2780模型中发挥细胞毒作用。总之，这些有希望的结果强烈表明有必要进行进一步的临床前评估，以测试这些新的金(III)配合物的临床潜力。
We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.