Polypyridyl ruthenium complexes have been intensively investigated for their remarkable antiproliferative properties and some are currently being tested in clinical trials. Here, we investigated the impact of illumination on the biological properties of a series of new cyclometalated ruthenium compounds with increased π-conjugation. We determined that various of these complexes display a bivalent biological activity as they are highly cytotoxic by themselves in absence of light while their cytotoxicity can significantly be elevated towards an IC50 in the nanomolar range upon illumination. In particular, we showed that these complexes are particularly active (IC50 < 1 μM) on two gastric cancer cell lines (AGS, KATO III) that are resistant towards cisplatin (IC50 > 25 μM). As expected, light activation leads to increased production of singlet oxygen species in vitro and accumulation of reactive oxygen species in vivo. Importantly, we established that light exposure shifts the mode of action of the complexes towards activation of a caspase 3-dependent apoptosis that correlates with increased DNA damage. Altogether, this study characterizes novel ruthenium complexes with dual activity that can be tuned towards different mode of action in order to bypass cancer cell resistance mechanisms.

中文翻译：

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环金属化钌配合物的光活化驱使caspase 3依赖性胃癌细胞凋亡。

聚吡啶钌复合物因其出色的抗增殖性能已得到深入研究，其中一些正在临床试验中。在这里，我们研究了照明对一系列π结合增加的新型环金属化钌化合物的生物学特性的影响。我们确定，这些复合物中的各种均表现出二价生物学活性，因为它们在缺乏光照的情况下自身具有高度的细胞毒性，而照射后其细胞毒性可显着提高至纳摩尔浓度的IC50。特别是，我们显示这些复合物在两种对顺铂耐药（IC50> 25μM）的胃癌细胞系（AGS，KATO III）上具有特别的活性（IC50 <1μM）。不出所料 光活化导致体外单线态氧种类的产生增加以及体内活性氧种类的积累。重要的是，我们确定了曝光使复合物的作用方式朝着激活caspase 3依赖性细胞凋亡的方向转变，而这种凋亡与DNA损伤的增加有关。总而言之，这项研究表征了具有双重活性的新型钌配合物，可以将其调配为不同的作用方式，从而绕过癌细胞的耐药机制。