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Updated: Jan 3, 2026
Evaluating the Role of Mitochondrial Function in Cancer-related Fatigue
Published on: May 17, 2018
Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial
Frances L Byrne1, Ellen M Olzomer1, Gabriella R Marriott1
1School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
Abstract:
A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD+ ratios exclusively in cancer cells, and induces necrosis. BH10 targets mitochondrial redox defence as evidenced by increased mitochondrial peroxiredoxin 3 oxidation and decreased mitochondrial aconitase activity, without changes in markers of cytosolic or nuclear damage. Over-expression of mitochondria-targeted catalase protects cells from BH10-mediated toxicity, while the thioredoxin reductase inhibitor auranofin synergistically enhances BH10-induced peroxiredoxin 3 oxidation and cytotoxicity. Overall, BH10 represents a 1,4-Naphthoquinone with an improved cancer-selective cytotoxicity profile via its mitochondrial specificity.
Insights
A novel 1,4-Naphthoquinone, BH10, selectively targets cancer cell metabolism and induces toxicity. This compound shows enhanced cancer-selective cytotoxicity compared to existing therapies by disrupting mitochondrial redox defense.
Area of Science:
- Biochemistry
- Cancer Biology
- Pharmacology
Background:
- Cancer cells exhibit altered nutrient metabolism, presenting a therapeutic target.
- Disrupting cancer cell metabolism can lead to cell death and offers a potential anti-cancer strategy.
Purpose of the Study:
- To identify molecules that disrupt cancer cell metabolism and exhibit selective toxicity.
- To characterize the anti-cancer properties and mechanism of action of a newly discovered compound, BH10.
Main Methods:
- Phenotypic chemical library screening to identify metabolic disruptors.
- Assessing cellular oxygen consumption rate and cytotoxicity across various cancer cell types.
- Investigating the effects of BH10 on metabolic pathways (glycolysis, glucose oxidation, redox balance) and mitochondrial function.
- Evaluating the impact of BH10 on specific cellular damage markers and synergistic effects with other compounds.
Main Results:
- Discovery of BH10, a 1,4-Naphthoquinone with broad-spectrum cancer cell toxicity.
- BH10 demonstrates superior cancer-selective toxicity compared to doxorubicin, 17-AAG, and vitamin K3.
- BH10 selectively alters cancer cell metabolism by increasing glucose oxidation, decreasing glycolysis, and lowering GSH:GSSG and NADPH/NADP+ ratios.
- BH10 specifically targets mitochondrial redox defense, indicated by increased peroxiredoxin 3 oxidation and decreased aconitase activity.
- Mitochondria-targeted catalase confers protection, while auranofin enhances BH10's toxicity.
Conclusions:
- BH10 is a potent 1,4-Naphthoquinone with significant cancer-selective cytotoxicity.
- BH10's mechanism involves the specific disruption of mitochondrial redox homeostasis in cancer cells.
- BH10 represents a promising therapeutic candidate for anti-cancer therapy due to its unique mechanism and improved selectivity.
