{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:41:13Z","timestamp":1785904873021,"version":"3.56.0"},"reference-count":52,"publisher":"Portland Press Ltd.","issue":"7","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:p>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 (Ki 2.5\u00a0\u03bcM) and co-operatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill coefficient values of 36\u201340\u00a0\u03bcM and 1.65\u20131.85 respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50 \u223c 7\u00a0\u03bcM) than other substrates including glutamate (IC50 \u223c 20\u00a0\u03bcM). In isolated DB-1 melanoma cells 1\u201310\u00a0\u03bcM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150\u00a0\u03bcM) decreased L-lactate output whereas increasing intracellular [L-lactate] &amp;gt; 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 on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor \u03b1-cyano-4-hydroxycinnamate (CHC).<\/jats:p>","DOI":"10.1042\/bj20151120","type":"journal-article","created":{"date-parts":[[2016,2,2]],"date-time":"2016-02-02T03:04:15Z","timestamp":1454382255000},"page":"929-936","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters"],"prefix":"10.1042","volume":"473","author":[{"given":"Bethany","family":"Nancolas","sequence":"first","affiliation":[{"name":"School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Guo","sequence":"additional","affiliation":[{"name":"Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania School of Medicine, B6 Blockley Hall, Philadelphia, PA 19104, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavindra","family":"Nath","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania School of Medicine, B6 Blockley Hall, Philadelphia, PA 19104, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David\u00a0S.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania School of Medicine, B6 Blockley Hall, Philadelphia, PA 19104, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis\u00a0B.","family":"Leeper","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian\u00a0A.","family":"Blair","sequence":"additional","affiliation":[{"name":"Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry\u00a0D.","family":"Glickson","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania School of Medicine, B6 Blockley Hall, Philadelphia, PA 19104, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew\u00a0P.","family":"Halestrap","sequence":"additional","affiliation":[{"name":"School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2016,3,29]]},"reference":[{"key":"2021112216364155000_B1","first-page":"418","article-title":"Anti-spermogenic activity of Lonidamine (AF-1890) in rabbit","volume":"5","author":"Cioli","year":"1980","journal-title":"Ultramicroscopy"},{"key":"2021112216364155000_B2","first-page":"1305","article-title":"Phase II study of lonidamine in patients with metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group Study","volume":"70","author":"Band","year":"1986","journal-title":"Cancer Treat. 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