Shpilt Zohar, Melamed-Book Naomi, Tshuva Edit Y
Institute of Chemistry, the Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
The Bio-Imaging Unit, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
J Inorg Biochem. 2023 Jun;243:112197. doi: 10.1016/j.jinorgbio.2023.112197. Epub 2023 Mar 20.
PhenolaTi is a promising Ti(IV) anticancer complex, with high stability and cytotoxicity, without notable toxic side-effects. Its cellular mechanism was proposed to relate to ER stress. Herein, we investigated the downstream effects of this mode of action in two cancer cell lines: ovarian carcinoma A2780 and cervical adenocarcinoma HeLa. First, although Ti(IV) is a non-redox metal, the formation of mitochondrial reactive oxygen species (ROS) was detected with live-cell imaging. Then, we inspected the effect of the mitochondrial ROS on cytotoxicity, using two methods: (a) addition of compounds that either elevate or reduce the mitochondrial glutathione concentration, thus affecting the oxidative state of the cells; and (b) scavenging mitochondrial ROS. Unlike the results observed for cisplatin, neither method influenced the cytotoxicity of phenolaTi, implying that ROS formation was a mere side effect of its activity. Additionally, live cell imaging displayed the hypoxia induced by phenolaTi, which can be associated with ROS formation. Overall, the results support the notion that ER-stress is the main cellular mechanism of phenolaTi, leading to hypoxia and mitochondrial ROS. The distinct mechanism of phenolaTi, which is different from that of cisplatin, combined with its stability and favorable anticancer properties, altogether make it a strong chemotherapeutic drug candidate.
酚钛是一种很有前景的四价钛抗癌复合物，具有高稳定性和细胞毒性，且无明显毒副作用。其细胞机制被认为与内质网应激有关。在此，我们研究了这种作用方式在两种癌细胞系中的下游效应：卵巢癌A2780和宫颈腺癌HeLa。首先，尽管四价钛是一种非氧化还原金属，但通过活细胞成像检测到了线粒体活性氧（ROS）的形成。然后，我们使用两种方法研究了线粒体ROS对细胞毒性的影响：（a）添加能提高或降低线粒体谷胱甘肽浓度从而影响细胞氧化状态的化合物；（b）清除线粒体ROS。与顺铂的结果不同，这两种方法均未影响酚钛的细胞毒性，这意味着ROS的形成只是其活性的一种副作用。此外，活细胞成像显示了酚钛诱导的缺氧，这可能与ROS的形成有关。总体而言，结果支持内质网应激是酚钛主要细胞机制的观点，该机制会导致缺氧和线粒体ROS。酚钛与顺铂不同的独特机制，再加上其稳定性和良好的抗癌特性，使其成为一种强大的化疗药物候选物。
