Miller Maya, Mellul Anna, Braun Maya, Sherill-Rofe Dana, Cohen Emiliano, Shpilt Zohar, Unterman Irene, Braitbard Ori, Hochman Jacob, Tshuva Edit Y, Tabach Yuval
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
iScience. 2020 Jul 24;23(7):101262. doi: 10.1016/j.isci.2020.101262. Epub 2020 Jun 12.
PhenolaTi is an advanced non-toxic anticancer chemotherapy; this inert bis(phenolato)bis(alkoxo) Ti(IV) complex demonstrates the intriguing combination of high and wide efficacy with no detected toxicity in animals. Here we unravel the cellular pathways involved in its mechanism of action by a first genome study on Ti(IV)-treated cells, using an attuned RNA sequencing-based available technology. First, phenolaTi induced apoptosis and cell-cycle arrest at the G2/M phase in MCF7 cells. Second, the transcriptome of the treated cells was analyzed, identifying alterations in pathways relating to protein translation, DNA damage, and mitochondrial eruption. Unlike for common metallodrugs, electrophoresis assay showed no inhibition of DNA polymerase activity. Reduced in vitro cytotoxicity with added endoplasmic reticulum (ER) stress inhibitor supported the ER as a putative cellular target. Altogether, this paper reveals a distinct ER-related mechanism by the Ti(IV) anticancer coordination complex, paving the way for wider applicability of related techniques in mechanistic analyses of metallodrugs.
酚钛是一种先进的无毒抗癌化疗药物；这种惰性的双（酚盐）双（烷氧基）钛（IV）配合物展现出高效且广谱的疗效与在动物体内未检测到毒性的有趣组合。在此，我们通过对经钛（IV）处理的细胞进行首次基因组研究，利用基于RNA测序的适配技术，揭示了其作用机制中涉及的细胞途径。首先，酚钛在MCF7细胞中诱导细胞凋亡并使细胞周期停滞在G2/M期。其次，对处理后细胞的转录组进行分析，确定了与蛋白质翻译、DNA损伤和线粒体爆发相关途径的改变。与常见金属药物不同，电泳分析显示DNA聚合酶活性未受抑制。添加内质网（ER）应激抑制剂后体外细胞毒性降低，这表明内质网是一个假定的细胞靶点。总之，本文揭示了钛（IV）抗癌配位配合物独特的内质网相关机制，为相关技术在金属药物作用机制分析中的更广泛应用铺平了道路。
