An anticancer Ti(IV) complex increases mitochondrial reactive oxygen species levels in relation with hypoxia and endoplasmic-reticulum stress: A distinct non DNA-related mechanism

Zohar Shpilt; Naomi Melamed-Book; Edit Y Tshuva

doi:10.1016/j.jinorgbio.2023.112197

An anticancer Ti(IV) complex increases mitochondrial reactive oxygen species levels in relation with hypoxia and endoplasmic-reticulum stress: A distinct non DNA-related mechanism

J Inorg Biochem. 2023 Jun:243:112197. doi: 10.1016/j.jinorgbio.2023.112197. Epub 2023 Mar 20.

Authors

Zohar Shpilt¹, Naomi Melamed-Book², Edit Y Tshuva³

Affiliations

¹ Institute of Chemistry, the Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
² The Bio-Imaging Unit, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
³ Institute of Chemistry, the Hebrew University of Jerusalem, Jerusalem 9190401, Israel.. Electronic address: Edit.tshuva@mail.huji.ac.il.

PMID: 36963201
DOI: 10.1016/j.jinorgbio.2023.112197

Abstract

PhenolaTi is a promising Ti(IV) anticancer complex, with high stability and cytotoxicity, without notable toxic side-effects. Its cellular mechanism was proposed to relate to ER stress. Herein, we investigated the downstream effects of this mode of action in two cancer cell lines: ovarian carcinoma A2780 and cervical adenocarcinoma HeLa. First, although Ti(IV) is a non-redox metal, the formation of mitochondrial reactive oxygen species (ROS) was detected with live-cell imaging. Then, we inspected the effect of the mitochondrial ROS on cytotoxicity, using two methods: (a) addition of compounds that either elevate or reduce the mitochondrial glutathione concentration, thus affecting the oxidative state of the cells; and (b) scavenging mitochondrial ROS. Unlike the results observed for cisplatin, neither method influenced the cytotoxicity of phenolaTi, implying that ROS formation was a mere side effect of its activity. Additionally, live cell imaging displayed the hypoxia induced by phenolaTi, which can be associated with ROS formation. Overall, the results support the notion that ER-stress is the main cellular mechanism of phenolaTi, leading to hypoxia and mitochondrial ROS. The distinct mechanism of phenolaTi, which is different from that of cisplatin, combined with its stability and favorable anticancer properties, altogether make it a strong chemotherapeutic drug candidate.

Keywords: Anticancer metallodrugs; Cisplatin; Endoplasmic reticulum stress; Hypoxia; Reactive oxygen species; Titanium(IV).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Line, Tumor
Cisplatin* / pharmacology
Endoplasmic Reticulum Stress
Female
Humans
Hypoxia
Ovarian Neoplasms*
Reactive Oxygen Species
Titanium

Substances

Reactive Oxygen Species
Cisplatin
Titanium