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

Abstract

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.

The design of small-molecule prodrugs and activatable phototherapeutics for cancer therapy

“…109,110 26 initially exhibited a low fluorescence emission at 510 nm in PBS buffer (pH 7.4), and the sequential addition of H 2 O 2 and GSH was shown to afford TPP-NH 2 ArSO 3 H, a process initiated by Nearly 50% of cancer patients with solid tumours will receive platinum (Pt)-based therapy. 111 The Pt(II)-based therapeutics that have been approved to treat cancers include cisplatin, carboplatin, nedaplatin, oxaliplatin, and lobaplatin. Unfortunately, their poor tumour specificity leads to dose-limiting toxicities and a narrow therapeutic index, severely limiting their clinical efficacy.…”

“…Nearly 50% of cancer patients with solid tumours will receive platinum (Pt)-based therapy. 111 The Pt( ii )-based therapeutics that have been approved to treat cancers include cisplatin, carboplatin, nedaplatin, oxaliplatin, and lobaplatin. Unfortunately, their poor tumour specificity leads to dose-limiting toxicities and a narrow therapeutic index, severely limiting their clinical efficacy.…”

Titanium complexes affectBacillus subtilisbiofilm formation

“…23 The exact mechanism of action of phenolaTi and related Ti(IV) complexes is still largely under investigations, with previous observations pointing to the participation of endoplasmic reticulum-(ER-) stress and hypoxia in tumor demise. [27][28][29][30] Several metal complexes have been shown to possess antibacterial activities. 31,32 In particular, it has been reported that Ti-based compounds inhibit the growth of Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa, 33 and TiO 2 nanoparticles generate reactive oxygen species which are lethal to bacteria.…”

Label-Free Target Identification Reveals the Anticancer Mechanism of a Rhenium Isonitrile Complex

“…The types of organic ligands in titanium-based complexes can alter their targets. ( Guo et al, 2000 ; Miller et al, 2020 ). Therefore, the ligand modification in metal-based complexes can significantly influence their engagement to different targets ( Meggers, 2007 ; Blanck et al, 2012 ).…”