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  3. A Photoactivated Ru (II) Polypyridine Complex Induced Oncotic Necrosis of A549 Cells by Activating Oxidative Phosphorylation and Inhibiting DNA Synthesis as Revealed by Quantitative Proteomics

A Photoactivated Ru (II) Polypyridine Complex Induced Oncotic Necrosis of A549 Cells by Activating Oxidative Phosphorylation and Inhibiting DNA Synthesis as Revealed by Quantitative Proteomics

  • Int J Mol Sci. 2023 Apr 24;24(9):7756. doi: 10.3390/ijms24097756.
Li Zhu 1,  Hui Liu 1 2,  Yang Dou 2 3,  Qun Luo 2 3,  Liangzhen Gu 2,  Xingkai Liu 2,  Qianxiong Zhou 4,  Juanjuan Han 2,  Fuyi Wang 2 3 5
Affiliations

Affiliations

  • 1 College of Applied Science and Technology, Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing 100101, China.
  • 2 Beijing National Laboratory for Molecular Sciences, CAS Research/Education Centre for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
  • 5 College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
PMID: 37175463 DOI: 10.3390/ijms24097756
Abstract

The ruthenium polypyridine complex [Ru(dppa)2(pytp)] (PF6)2 (termed as ZQX-1), where dppa = 4,7-diphenyl-1,10-phenanthroline and pytp = 4'-pyrene-2,2':6',2''-terpyridine, has been shown a high and selective cytotoxicity to hypoxic and cisplatin-resistant Cancer cells either under irradiation with blue light or upon two-photon excitation. The IC50 values of ZQX-1 towards A549 Cancer cells and HEK293 health cells are 0.16 ± 0.09 µM and >100 µM under irradiation at 420 nm, respectively. However, the mechanism of action of ZQX-1 remains unclear. In this work, using the quantitative proteomics method we identified 84 differentially expressed proteins (DEPs) with |fold-change| ≥ 1.2 in A549 Cancer cells exposed to ZQX-1 under irradiation at 420 nm. Bioinformatics analysis of the DEPs revealed that photoactivated ZQX-1 generated Reactive Oxygen Species (ROS) to activate Oxidative Phosphorylation signaling to overproduce ATP; it also released ROS and pyrene derivative to damage DNA and arrest A549 cells at S-phase, which synergistically led to oncotic necrosis and Apoptosis of A549 cells to deplete excess ATP, evidenced by the elevated level of PRAP1 and cleaved capase-3. Moreover, the DNA damage inhibited the expression of DNA repair-related proteins, such as RBX1 and GPS1, enhancing photocytotoxicity of ZQX-1, which was reflected in the inhibition of Integrin signaling and disruption of ribosome assembly. Importantly, the photoactivated ZQX-1 was shown to activate hypoxia-inducible factor 1A (HIF1A) survival signaling, implying that combining use of ZQX-1 with HIF1A signaling inhibitors may further promote the photocytotoxicity of the prodrug.

Keywords

DNA damage; oncotic necrosis; photoactivated chemotherapy; quantitative proteomics; reactive oxygen species; ruthenium polypyridine complex.

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