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Published on: January 5, 2024
A new gold(I) phosphine complex induces apoptosis in prostate cancer cells by increasing reactive oxygen species
Yuan Wang1,2, Haokun Yuan3, Ruiqin Fang4
1The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, School of Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. wangyuan_med@uestc.edu.cn.
Abstract:
Thioredoxin reductase (TrxR) is a pivotal regulator of redox homeostasis. It is frequently overexpressed in various cancer cells, including prostate cancer, making it a promising target for the development of anti-cancer drugs. In this study, we screened a series of newly designed complexes of gold(I) phosphine. Specifically, Compound 5 exhibited the highest cytotoxicity against prostate cancer cells and demonstrated stronger antitumor effects than commonly used drugs, such as cisplatin and auranofin. Importantly, our mechanistic study revealed that Compound 5 effectively inhibits the TrxR system in vitro. Additionally, Compound 5 promoted intracellular accumulation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and irreversible apoptosis in prostate cancer cells. Our in vivo xenograft study further demonstrated that Compound 5 has excellent antitumor activity against prostate cancer cells, but does not cause severe side effects. These findings provide a promising lead Compound for the development of novel antitumor agents targeting prostate cancer and offer a valuable tool for investigating biological pathways involving TrxR and ROS modulation.
Insights
A novel gold(I) phosphine complex, Compound 5, effectively targets prostate cancer by inhibiting thioredoxin reductase (TrxR) and inducing cancer cell death. This compound shows potent antitumor activity with minimal side effects in preclinical studies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Thioredoxin reductase (TrxR) is crucial for redox balance and often overexpressed in cancers like prostate cancer.
- TrxR is a validated therapeutic target for novel anti-cancer drug development.
Purpose of the Study:
- To screen gold(I) phosphine complexes for anti-prostate cancer activity.
- To investigate the mechanism of action of the most potent compound.
- To evaluate the in vivo efficacy and safety of the lead compound.
Main Methods:
- Screening of novel gold(I) phosphine complexes against prostate cancer cell lines.
- In vitro assessment of TrxR inhibition and reactive oxygen species (ROS) generation.
- Mitochondrial dysfunction and apoptosis assays.
- In vivo efficacy studies using xenograft models.
Main Results:
- Compound 5 demonstrated superior cytotoxicity against prostate cancer cells compared to cisplatin and auranofin.
- Compound 5 effectively inhibited TrxR activity in vitro.
- Compound 5 induced ROS accumulation, mitochondrial dysfunction, and apoptosis in cancer cells.
- Compound 5 exhibited significant antitumor activity in vivo with no observed severe side effects.
Conclusions:
- Compound 5 is a promising lead candidate for novel prostate cancer therapeutics targeting the TrxR system.
- Compound 5 offers a potential new strategy for cancer treatment by modulating TrxR and ROS pathways.
- Further investigation of Compound 5 could provide insights into TrxR-mediated redox regulation in cancer.
