Anti-neoplastic activity of phenolaTi: Ti tackles the Endoplasmic Reticulum through PERK and IRE1 pathways

Maya Miller ¹ Anna Mellul ¹ Maya Braun ¹ Dana Sherill-Rofe ¹ Emiliano Cohen ¹ Zohar Shpilt ² Jacob Hochman ³ Edit Y. Tshuva ² Yuval Tabach ¹

¹Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Israel
²Institute of Chemistry, The Hebrew University of Jerusalem, Israel
³Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Israel

Metallodrugs, i.e. pharmaceuticals which contain metals, are essential anticancer agents with proven efficacy towards a variety of tumors. Titanium based drug, namely phenolaTi, is a novel anti-neoplastic agent that demonstrates high and wide efficacy, low toxicity, and enhanced hydrolytic stability. We present the first attempt to uncover phenolaTi mechanism of action by mapping its effect on the transcriptome followed by cellular phenotypic changes in MCF7 cells treated at different time points. Results indicate major alterations in essential signaling pathways such as cell cycle, protein translation, DNA damage, mitochondrial eruption, and p53 regulation. Biochemical analysis supports cell cycle arrest at G2/M phase, and apoptosis initiation. No inhibition of DNA polymerase activity was documented, in contrast to other metallodrugs, impling a distinct mechansim of action. Loss of in vitro cytotoxicity of the drug was observed in the presence of an endoplasmic reticulum (ER) stress inhibitor, salubrinal, pointing to the ER as a putative cellular target. Moreover, biochemical studies have shown cellular response through PERK and p-IRE1 pathways. Altogether, we present the first in depth study of cellular response to a Ti(IV) phenolato compound.