Allison Simon J, Sadiq Maria, Baronou Efstathia, Cooper Patricia A, Dunnill Chris, Georgopoulos Nikolaos T, Latif Ayşe, Shepherd Samantha, Shnyder Steve D, Stratford Ian J, Wheelhouse Richard T, Willans Charlotte E, Phillips Roger M
School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK.
Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK.
Cancer Lett. 2017 Sep 10;403:98-107. doi: 10.1016/j.canlet.2017.04.041. Epub 2017 Jun 15.
Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting.
有机金属配合物为靶向作用于癌症生物学中多个重要途径提供了可能。在此，对一种双（N - 杂环卡宾）银配合物（Ag8）的临床前活性及作用机制进行了评估。Ag8通过多种机制诱导DNA损伤，包括抑制拓扑异构酶I/II和硫氧还蛋白还原酶以及诱导活性氧生成。DNA损伤诱导与对增殖细胞观察到的细胞毒性一致，且Ag8通过凋亡诱导细胞死亡。Ag8还抑制DNA修复酶PARP1，对顺铂耐药的A2780细胞表现出优先活性，并增强替莫唑胺的活性。Ag8对非增殖性非癌细胞的活性显著较低，并选择性抑制癌细胞中的糖酵解。Ag8对中空纤维中腹腔内植入的细胞也诱导了显著的抗肿瘤作用，但对皮下植入的中空纤维缺乏活性。因此，Ag8靶向癌症生物学中多个重要途径，对非癌细胞活性较低，并在局部区域环境中显示出体内活性。
