Deciphering Molecular Pathways and Cellular Interactions Initiated by Anticancer Ti(IV) Phenolato Complexes

Metal containing compounds have entered the field of anticancer research with the introduction of cisplatin in the early 70^th, followed by titanium complexes a decade later. Unlike platinum, titanium is a biocompatable metal providing a clear advantage for the use in therapy. The first class of titanium containing drugs introduced suffered from rapid hydrolysis in biological environment, which hampered the identification of the active species and the study of its molecular mechanism, thus ultimately resulting in failure in clinical trials. Later titanium complexes based on phenolato ligands achieved enhanced resistance to hydrolysis;¹ these compounds have shown high anti-tumor activity toward various cancer cell lines, selectivity to cancer tissue, durability in aquatic solutions and effectiveness in in vivo models.

This work aims to promote our understanding of the molecular mechanism involved in the activity of Ti(IV) phenolato complexes. A leading phenolato Ti(IV) compound influenced the cell cycle, causing G1 arrest. Cytotoxicity measurements have shown significant decrease in cell viability only within 24 hours of incubation, supporting a programmed rather than instant cell death. Additionally, upregulation of p53 and caspase9 proteins imply on apoptotic pathways involved. Comparing cytotoxicity, cellular uptake, and protein levels in two cell lines imply that different mechanisms are plausible.² Additional experiments suggest that chromosomal DNA and/or mitochondria may serve as cellular targets for this class of complexes. Preliminary results with chiral complexes will also be presented. Altogether, the preliminary mechanistic insights gained should advance these promising Ti(IV) phenolato complexes for the use in cancer treatment.

References:

Miller M; Tshuva E.Y.; Eur. J. Inorg. Chem. (2014) 9, 1485.
Miller M; Braitbard O.; Hochman J.; Tshuva E.Y.; J. Inorg. Biochem. (2016) 163, 250-257.