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Updated: Aug 23, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Developing Bi-Gold Compound BGC2a to Target Mitochondria for the Elimination of Cancer Cells
Qingbin Cui1, Wenwen Ding1, Panpan Liu1
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Abstract:
Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin's positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds' major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity.
Insights
New gold compounds targeting mitochondria show potent anti-cancer effects. Bi-gold compounds, like BGC2a, disrupt mitochondrial function and suppress tumor growth, offering a promising strategy for developing novel cancer therapeutics.
Area of Science:
- Biomedical Science
- Drug Discovery
- Cancer Research
Background:
- Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are crucial for cancer cell survival, particularly cancer stem cells (CSCs), which drive drug resistance and relapse.
- Auranofin, a repurposed anti-rheumatic drug, exhibits anticancer activity by inducing ROS and mitochondrial dysfunction.
- Enhancing mitochondria-targeting capacity of gold compounds may improve their anticancer efficacy.
Purpose of the Study:
- To design and evaluate mono-gold and bi-gold compounds with enhanced mitochondria-targeting capacity.
- To investigate the mechanism of action of these compounds, focusing on ROS induction and mitochondrial dysfunction.
- To assess the in vitro and in vivo anticancer efficacy of the most potent compounds.
Main Methods:
- Synthesis and characterization of mono-gold and bi-gold compounds.
- Assessment of cancer cell proliferation, ROS levels, and apoptosis induction.
- Mitochondrial function assays including oxygen consumption rate, membrane potential, and ATP production.
- Evaluation of colony formation, side population (SP) cells, and tumor growth in xenograft models.
Main Results:
- Bi-gold compounds generally exhibited superior cancer cell proliferation suppression compared to mono-gold compounds.
- The potent bi-gold compound BGC2a inhibited TrxR, increased cellular ROS, and induced apoptosis, independent of vitamin C reversal.
- BGC2a accumulated in mitochondria, leading to dysfunction (reduced oxygen consumption, membrane potential, and ATP production), inhibited colony formation, reduced SP cells, and suppressed tumor growth in vivo.
Conclusions:
- Mitochondrial dysfunction is a key lethal mechanism for gold-based anticancer compounds.
- Increasing the mitochondria-targeting capacity of gold compounds enhances their anticancer efficacy.
- This study provides a novel approach for developing potent gold-based anticancer drugs by targeting mitochondria.
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