Titanium Tackles the Endolplasmic Reticulum: A First Genomic Study on a Titanium Anticacner Metallodrug

PhenolaTi is novel 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-Seq-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, mitochondrial eruption, and p53 regulation. 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. Overall design: The effect of phenolaTi (drug) on MCF7 cell at 54uM concetration was examined over 6 time points at triplicates. Overall, after 0,3,6,15,24 and 48 hours of incubation. Sample 0 is a control, with untreated cells. Overall 18 samples.