A Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer

J Med Chem, 2023 · DOI: 10.1021/acs.jmedchem.3c00238 · Published: June 22, 2023

Simple Explanation

This research focuses on creating and testing new gold-based compounds to fight aggressive cancers, particularly triple-negative breast cancer (TNBC). The scientists designed several gold(III) complexes and found one, called Au-3, that effectively stops tumor growth in mice. The study showed that Au-3 is stable in blood serum, meaning it can last long enough in the body to reach the tumor. Au-3 works by disrupting the energy production process in cancer cells, specifically by causing mitochondrial uncoupling, which weakens and eventually kills the cancer cells. The researchers also found that Au-3 is more effective at targeting cancer cells than healthy cells, suggesting it could be a promising new treatment option with fewer side effects. This is the first time a gold compound has been shown to both uncouple mitochondria and inhibit tumor growth in a living organism.

Study Duration

Not specified

Participants

Balb/c mice

Evidence Level

Level Not specified, In vivo study and in vitro experiments

Key Findings

1
The gold(III) complex Au-3 exhibits significant tumor growth inhibition in a metastatic TNBC mouse model.
2
Au-3 displays promising blood serum stability over 24 h and alters in the presence of excess L-GSH.
3
Au-3 induces mitochondrial uncoupling, membrane depolarization, G1 cell cycle arrest, and prompts apoptosis.

Research Summary

This study introduces novel biphenyl Au(III) complexes with bisphosphine ligands, demonstrating their stability and mild mitochondrial uncoupling activity. The complex Au-3 exhibits potent anticancer activity against aggressive cancer cells, including TNBC and glioblastoma cells, and inhibits TNBC tumor growth in vivo. The research highlights Au-3 as the first account of Au(III) complexes to induce mitochondrial uncoupling and inhibit tumor growth in vivo, suggesting a promising avenue for developing safe metal-based uncouplers.

Practical Implications

Drug Development

Au-3 provides a framework for developing safe metal-based uncouplers for cancer treatment.

Therapeutic Value

The study fortifies the therapeutic value of organometallic gold agents in cancer therapy.

Clinical Relevance

The significant stability of Au-3 in blood serum enhances its potential for clinical translation.

Study Limitations

1
Biodistribution studies show significant accumulation in kidneys and liver, which suggest that these organs may be the major clearance hubs of Au-3.
2
Further studies needed to fully elucidate the long-term toxicity profile of Au-3.
3
The exact mechanisms of selectivity of Au-3 towards cancer cells over healthy cells require further investigation.

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