Titanium Tackles the Endoplasmic Reticulum: A First Genomic Study on a Titanium Anticancer Metallodrug

• Published in: iScience 2020-07, Vol.23 (7), p.101262, Article 101262
• Main Authors: Miller, Maya, Mellul, Anna, Braun, Maya, Sherill-Rofe, Dana, Cohen, Emiliano, Shpilt, Zohar, Unterman, Irene, Braitbard, Ori, Hochman, Jacob, Tshuva, Edit Y., Tabach, Yuval
• Format: Article
• Language: English
• Subjects: Biochemistry; Cancer; Genomics; Organometallic Chemistry
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101262

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. [Display omitted] •First in-depth mechanistic analysis of a non-toxic Ti-based anticancer metallodrug•A comprehensive RNA-seq analysis to map the transcriptomic netowrk initiated by phenolaTi.•Unraveling a distinct mechanism through ER stress, not through direct DNA binding•Toward understanding and applicability of diverse better-tolerable chemotherapies Organometallic Chemistry; Biochemistry; Genomics; Cancer