8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin

Minying Huang; Yuqing Zhang; Yao Gong; Zhijun Liang; Xide Chen; Yunxin Ni; Xinjie Pan; Wei Wu; Jiaxi Chen; Zunnan Huang; Jing Sun

doi:10.1016/j.jinorgbio.2023.112365

8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin

J Inorg Biochem. 2023 Nov:248:112365. doi: 10.1016/j.jinorgbio.2023.112365. Epub 2023 Sep 4.

Authors

Minying Huang¹, Yuqing Zhang¹, Yao Gong¹, Zhijun Liang¹, Xide Chen², Yunxin Ni¹, Xinjie Pan¹, Wei Wu¹, Jiaxi Chen³, Zunnan Huang⁴, Jing Sun⁵

Affiliations

¹ School of Pharmacy, Guangdong Medical University, Dongguan 523808, China.
² The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China. Electronic address: chenxide@gdmu.edu.cn.
³ School of Pharmacy, Guangdong Medical University, Dongguan 523808, China. Electronic address: jiaxi@gdmu.edu.cn.
⁴ Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan 523808, China.
⁵ School of Pharmacy, Guangdong Medical University, Dongguan 523808, China; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan 523808, China; The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China. Electronic address: sunjing03@foxmail.com.

PMID: 37690267
DOI: 10.1016/j.jinorgbio.2023.112365

Abstract

Ruthenium complexes are one of the most promising anticancer drugs triggered extensive research. Here, the synthesis and characterization of two ruthenium(II) polypyridine complexes containing 8-hydroxylquinoline as ligand, [Ru(dip)₂(8HQ)]PF₆ (Ru1), [Ru(dpq)₂(8HQ)]PF₆ (Ru2) (8HQ = 8-hydroxylquinoline; dip = 4,7-diphenyl-1,10-phenanthroline; dpq = pyrazino[2,3-f][1,10]phenanthroline) were reported. On the basis of cytotoxicity tests, Ru1 (IC₅₀ = 1.98 ± 0.02 μM) and Ru2 (IC₅₀ = 10.02 ± 0.19 μM) both showed good anticancer activity in a panel of cell lines, especially in HeLa cells. Researches on mechanism indicated that Ru1 and Ru2 acted on mitochondria and nuclei and induced reactive oxygen species (ROS) accumulation, while the morphology of nuclei and cell cycle had no significant change. Western blot assay further proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in HeLa cells. In addition, the toxicity test of zebrafish embryos showed that the concentrations of Ru1 and Ru2 below 120 μM and 60 μM were safe and did not have obvious effect on the normal development of zebrafish embryos.

Keywords: 8-hydroxylquinoline; Anticancer; Ferroptosis; GPX4; ROS; Ru(II) complexes.

Publication types

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

MeSH terms

Animals
Ferritins
Ferroptosis*
HeLa Cells
Humans
Oxyquinoline
Ruthenium*
Zebrafish

Substances

Ferritins
Ruthenium
Oxyquinoline