title: Mechanism of antineoplastic activity of lonidamine.
abstract: Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited 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). Recent studies have demonstrated that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki2.5μM) and cooperatively inhibits l-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5and Hill coefficient values of 36-40μM 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 (IC50~7μM) than other substrates including glutamate (IC50~20μM). LND inhibits the succinate-ubiquinone reductase activity of respiratory Complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through Complex II and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. 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, Complex II and glutamine/glutamate oxidation.
authors: Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: kavindra.nath@uphs.upenn.edu.
authors: Kavindra
authors: K
authors: Nath
authors: Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Lili
authors: L
authors: Guo
authors: School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD, UK.
authors: Bethany
authors: B
authors: Nancolas
authors: Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: David S
authors: DS
authors: Nelson
authors: Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Alexander A
authors: AA
authors: Shestov
authors: Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Seung-Cheol
authors: SC
authors: Lee
authors: Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Jeffrey
authors: J
authors: Roman
authors: Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Rong
authors: R
authors: Zhou
authors: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Dennis B
authors: DB
authors: Leeper
authors: School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD, UK.
authors: Andrew P
authors: AP
authors: Halestrap
authors: Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Ian A
authors: IA
authors: Blair
authors: Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Jerry D
authors: JD
authors: Glickson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006593:Hexokinase / Q000037:antagonists & inhibitors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007191:Indazoles / Q000494:pharmacology* / Q000633:toxicity; D026901:Membrane Transport Proteins / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; C573718:MPC1 protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D019289:Pyruvic Acid; D006593:Hexokinase; C016371:lonidamine
keywords: (31)P and (1)H magnetic resonance spectroscopy; Breast cancer; Doxorubicin; Electron transport chain; Lonidamine; Melanoma; Melphalan; Mitochondrial pyruvate carrier; Monocarboxylate transporter; Ovarian cancer; Prostate cancer; Tumor acidification; Tumor bioenergetics; Xenografts