ArticleThe Biochemical journal2016
The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters.
Article in The Biochemical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 121 citations in OpenAlex.
- Recent progress in small molecules targeting the acidic tumor microenvironment.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease.Journal of pharmaceutical analysis · 2026Review
- Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review).International journal of molecular medicine · 2026Review
- Article
- Lactate at the crossroads of tumor metabolism and immune escape: a new frontier in cancer therapy.Journal of translational medicine · 2025Review
- Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.Science advances · 2025Article
- Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier.European journal of medicinal chemistry · 2025Article
- Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications.Biomolecules · 2025Review
- Article
- Article
- Lactate: a rising star in tumors and inflammation.Frontiers in immunology · 2024Review
- Exploring monocarboxylate transporter inhibition for cancer treatment.Exploration of targeted anti-tumor therapy · 2024Review
- The Plasma Membrane Monoamine Transporter is Highly Expressed in Neuroblastoma and Functions as an mIBG Transporter.The Journal of pharmacology and experimental therapeutics · 2023Article
- The role of lactate in cardiovascular diseases.Cell communication and signaling : CCS · 2023Review
- Targeting mitochondrial energetics reverses panobinostat- and marizomib-induced resistance in pediatric and adult high-grade gliomas.Molecular oncology · 2023Article
- Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment.Journal of translational medicine · 2023Article
- Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition.Acta physiologica (Oxford, England) · 2023Review
- pH-dependent structural characteristics of lonidamine:RSC advances · 2023Article
- The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease.Biomolecules · 2023Review
- Long noncoding RNAs: glycolysis regulators in gynaecologic cancers.Cancer cell international · 2023Review
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitizing tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, whereas indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). In the present study, we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki2.5 μM) and co-operatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevisoocytes with K0.5 and Hill coefficient values of 36-40 μM and 1.65-1.85 respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50~ 7 μM) than other substrates including glutamate (IC50~ 20 μM). In isolated DB-1 melanoma cells 1-10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output whereas increasing intracellular [L-lactate] > 5-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND onL-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate (CHC).
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