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

Maya Miller; Anna Mellul; Maya Braun; Dana Sherill-Rofe; Emiliano Cohen; Zohar Shpilt; Irene Unterman; Ori Braitbard; Jacob Hochman; Edit Y Tshuva; Yuval Tabach

doi:10.1016/j.isci.2020.101262

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

iScience. 2020 Jul 24;23(7):101262. doi: 10.1016/j.isci.2020.101262. Epub 2020 Jun 12.

Authors

Affiliations

¹ Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
² Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
³ Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
⁴ Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
⁵ Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: edit.tshuva@mail.huji.ac.il.
⁶ Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel. Electronic address: yuvaltab@ekmd.huji.ac.il.

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.

Keywords: Biochemistry; Cancer; Genomics; Organometallic Chemistry.