Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

Guan-Dong Zhang; Meng-Meng Wang; Yan Su; Hongbao Fang; Xu-Ling Xue; Hong-Ke Liu; Zhi Su

doi:10.1016/j.jinorgbio.2024.112574

Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

J Inorg Biochem. 2024 Jul:256:112574. doi: 10.1016/j.jinorgbio.2024.112574. Epub 2024 Apr 23.

Authors

Guan-Dong Zhang¹, Meng-Meng Wang¹, Yan Su², Hongbao Fang¹, Xu-Ling Xue¹, Hong-Ke Liu³, Zhi Su⁴

Affiliations

¹ Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
² Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China; Department of Rheumatology and Immunology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China. Electronic address: suyanahnu@163.com.
³ Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: liuhongke@njnu.edu.cn.
⁴ Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: zhisu@njnu.edu.cn.

PMID: 38677004
DOI: 10.1016/j.jinorgbio.2024.112574

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh₃, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh₃ exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC₅₀ value of 4.0 μM. Ru-TPE-PPh₃ could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh₃ also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.

Keywords: Anti-cancer; Autophagy; CuAAC; Ru-arene complex; Triple negative breast cancer.

Publication types

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

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Autophagy* / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Coordination Complexes* / chemical synthesis
Coordination Complexes* / chemistry
Coordination Complexes* / pharmacology
Female
Humans
Membrane Potential, Mitochondrial / drug effects
Mitochondria* / drug effects
Mitochondria* / metabolism
Reactive Oxygen Species* / metabolism
Ruthenium* / chemistry
Ruthenium* / pharmacology
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology

Substances

Coordination Complexes
Ruthenium
Antineoplastic Agents
Reactive Oxygen Species