AI Article Synopsis
- Mitochondrial uncouplers are being studied for their potential to treat cancer, showing promising anti-cancer effects in preclinical models, both alone and in combination therapies.
- These agents may selectively target cancer cells more effectively than normal cells by disrupting metabolic pathways and reducing ATP levels, though the impact on reactive oxygen species varies among different uncouplers.
- Despite the encouraging research, the long-term safety of mitochondrial uncouplers is still uncertain, and further studies are needed to determine the best patient populations and cancer types that could benefit from these treatments.
Article Abstract
Background: Mitochondrial uncouplers are well-known for their ability to treat a myriad of metabolic diseases, including obesity and fatty liver diseases. However, for many years now, mitochondrial uncouplers have also been evaluated in diverse models of cancer in vitro and in vivo. Furthermore, some mitochondrial uncouplers are now in clinical trials for cancer, although none have yet been approved for the treatment of cancer.
Scope Of Review: In this review we summarise published studies in which mitochondrial uncouplers have been investigated as an anti-cancer therapy in preclinical models. In many cases, mitochondrial uncouplers show strong anti-cancer effects both as single agents, and in combination therapies, and some are more toxic to cancer cells than normal cells. Furthermore, the mitochondrial uncoupling mechanism of action in cancer cells has been described in detail, with consistencies and inconsistencies between different structural classes of uncouplers. For example, many mitochondrial uncouplers decrease ATP levels and disrupt key metabolic signalling pathways such as AMPK/mTOR but have different effects on reactive oxygen species (ROS) production. Many of these effects oppose aberrant phenotypes common in cancer cells that ultimately result in cell death. We also highlight several gaps in knowledge that need to be addressed before we have a clear direction and strategy for applying mitochondrial uncouplers as anti-cancer agents.
Major Conclusions: There is a large body of evidence supporting the therapeutic use of mitochondrial uncouplers to treat cancer. However, the long-term safety of some uncouplers remains in question and it will be critical to identify which patients and cancer types would benefit most from these agents.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129951 | PMC |
| http://dx.doi.org/10.1016/j.molmet.2021.101222 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Metabolic Signaling in the Tumor Microenvironment.
Cancers (Basel)
January 2025
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation.
View Article and Find Full Text PDFMitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth.
Cell Rep Med
December 2024
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address:
Mitochondrial uncouplers dissipate proton gradients and deplete ATP production from oxidative phosphorylation (OXPHOS). While the growth of prostate cancer depends on OXPHOS-generated ATP, the oncogenic pathway mediated by the transcription factor E2F1 is crucial for the progression of this deadly disease. Here, we report that mitochondrial uncouplers, including tizoxanide (TIZ), the active metabolite of the Food and Drug Administration (FDA)-approved anthelmintic nitazoxanide (NTZ), inhibit E2F1-mediated expression of genes involved in cell cycle progression, DNA synthesis, and lipid synthesis.
View Article and Find Full Text PDFBone marrow mesenchymal stem cells ameliorate diet-induced obesity by activating thermogenesis and alleviating inflammation in adipose tissue.
Biochem Biophys Res Commun
December 2024
Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, PR China. Electronic address:
Obesity and its related metabolic disorders seriously threaten our health and significantly reduce our life expectancy. The aim of the present study was to explore the effects of bone marrow mesenchymal stem cells (BMSCs) on high-fat diet (HFD)-induced obesity mice. The results demonstrated that BMSCs significantly reduced body weight, improved glucose tolerance and insulin sensitivity in obese mice.
View Article and Find Full Text PDFIdentification of a distal enhancer of Ucp1 essential for thermogenesis and mitochondrial function in brown fat.
Commun Biol
January 2025
State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.
Uncoupling protein 1 (UCP1) is a crucial protein located in the mitochondrial inner membrane that mediates nonshivering thermogenesis. However, the molecular mechanisms by which enhancer-promoter chromatin interactions control Ucp1 transcriptional regulation in brown adipose tissue (BAT) are unclear. Here, we employed circularized chromosome conformation capture coupled with next-generation sequencing (4C-seq) to generate high-resolution chromatin interaction profiles of Ucp1 in interscapular brown adipose tissue (iBAT) and epididymal white adipose tissue (eWAT) and revealed marked changes in Ucp1 chromatin interaction between iBAT and eWAT.
View Article and Find Full Text PDFα-Ketoisocaproic Acid Disrupts Mitochondrial Bioenergetics in the Brain of Neonate Rats: Molecular Modeling Studies of α-ketoglutarate Dehydrogenase Subunits Inhibition.
Neurochem Res
January 2025
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Brain accumulation of the branched-chain α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) occurs in maple syrup urine disease (MSUD), an inherited intoxicating metabolic disorder caused by defects of the branched-chain α-keto acid dehydrogenase complex. Patients commonly suffer life-threatening acute encephalopathy in the newborn period and develop chronic neurological sequelae of still undefined pathogenesis. Therefore, this work investigated the in vitro influence of pathological concentrations of KIC (5 mM), KMV (1 mM), and KIV (1 mM) on mitochondrial bioenergetics in the cerebral cortex of neonate (one-day-old) rats.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!