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Biochim Biophys Acta
2016 Dec 01;18662:151-162. doi: 10.1016/j.bbcan.2016.08.001.
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Mechanism of antineoplastic activity of lonidamine.
Nath K
,
Guo L
,
Nancolas B
,
Nelson DS
,
Shestov AA
,
Lee SC
,
Roman J
,
Zhou R
,
Leeper DB
,
Halestrap AP
,
Blair IA
,
Glickson JD
.
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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 (Ki 2.5μM) and cooperatively inhibits l-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and 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.
Amadori,
Modulating effect of lonidamine on response to doxorubicin in metastatic breast cancer patients: results from a multicenter prospective randomized trial.
1998, Pubmed
Amadori,
Modulating effect of lonidamine on response to doxorubicin in metastatic breast cancer patients: results from a multicenter prospective randomized trial.
1998,
Pubmed
Atema,
Potentiation of DNA-adduct formation and cytotoxicity of platinum-containing drugs by low pH.
1993,
Pubmed
Ben-Horin,
Mechanism of action of the antineoplastic drug lonidamine: 31P and 13C nuclear magnetic resonance studies.
1995,
Pubmed
Ben-Yoseph,
Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification.
1998,
Pubmed
Berruti,
Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design.
2002,
Pubmed
Blair,
Endogenous glutathione adducts.
2006,
Pubmed
Bottalico,
Correlation between HPLC-determined lonidamine serum levels and clinical response in patients with advanced ovarian cancer.
1996,
Pubmed
Buccheri,
A randomised trial of MACC chemotherapy with or without lonidamine in advanced non-small cell lung cancer. Cuneo Lung Cancer Study Group (CuLCaSG).
1994,
Pubmed
Burd,
Tumor oxygenation and acidification are increased in melanoma xenografts after exposure to hyperglycemia and meta-iodo-benzylguanidine.
2003,
Pubmed
Calabresi,
Fluorouracil, doxorubicin, and cyclophosphamide versus fluorouracil, doxorubicin, and cyclophosphamide plus lonidamine for the treatment of advanced breast cancer: a multicentric randomized clinical study.
1991,
Pubmed
Cervantes-Madrid,
Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids.
2015,
Pubmed
Chu,
The role of low intracellular or extracellular pH in sensitization to hyperthermic radiosensitization.
1988,
Pubmed
Chu,
The role of intracellular pH and its variance in low pH sensitization of killing by hyperthermia.
1990,
Pubmed
Colella,
Randomised phase II study of methotrexate (MTX) versus methotrexate plus lonidamine (MTX + LND) in recurrent and/or metastatic carcinoma of the head and neck.
1994,
Pubmed
Comella,
Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non-small-cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group.
1999,
Pubmed
Contu,
Lonidamine in non-small-cell lung cancer: a phase II study.
1991,
Pubmed
De Lena,
Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study.
2001,
Pubmed
De Lena,
Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum.
1997,
Pubmed
De Marinis,
The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Italian Lung Cancer Task Force.
1999,
Pubmed
Di Cosimo,
Lonidamine: efficacy and safety in clinical trials for the treatment of solid tumors.
2003,
Pubmed
Dogliotti,
Cisplatin, epirubicin, and lonidamine combination regimen as first-line chemotherapy for metastatic breast cancer: a pilot study.
1998,
Pubmed
Dogliotti,
Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial.
1996,
Pubmed
Dröse,
Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning.
2013,
Pubmed
Evans,
Metformin and reduced risk of cancer in diabetic patients.
2005,
Pubmed
Floridi,
Changes of energy metabolism in the germ cells and Ehrlich ascites tumor cells.
1981,
Pubmed
Floridi,
Enhancement of doxorubicin content by the antitumor drug lonidamine in resistant Ehrlich ascites tumor cells through modulation of energy metabolism.
1998,
Pubmed
Floridi,
Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells.
1981,
Pubmed
Floridi,
Modulation of glycolysis in neuroepithelial tumors.
1989,
Pubmed
Floridi,
Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells.
1981,
Pubmed
Floridi,
Action of the antitumor and antispermatogenic agent lonidamine on electron transport in Ehrlich ascites tumor mitochondria.
1983,
Pubmed
Franciosi,
Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review.
2013,
Pubmed
Gadducci,
Epidoxorubicin and lonidamine in refractory or recurrent epithelial ovarian cancer.
1994,
Pubmed
Gatzemeier,
Single- and multiple dose pharmacokinetics of lonidamine in patients suffering from non-small-cell lung cancer.
1991,
Pubmed
Gatzemeier,
Phase III trial with and without lonidamine in non-small cell lung cancer.
1991,
Pubmed
Gebbia,
Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM).
1997,
Pubmed
Gerweck,
Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer.
1996,
Pubmed
Golding,
Targeting tumour energy metabolism potentiates the cytotoxicity of 5-aminolevulinic acid photodynamic therapy.
2013,
Pubmed
Guo,
Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.
2016,
Pubmed
Halestrap,
The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation.
1999,
Pubmed
,
Xenbase
Halestrap,
The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors.
1975,
Pubmed
Halestrap,
Monocarboxylic acid transport.
2013,
Pubmed
Ianniello,
Cisplatin, epirubicin, and vindesine with or without lonidamine in the treatment of inoperable nonsmall cell lung carcinoma: a multicenter randomized clinical trial.
1996,
Pubmed
Jähde,
Hydrogen ion-mediated enhancement of cytotoxicity of bis-chloroethylating drugs in rat mammary carcinoma cells in vitro.
1989,
Pubmed
Jähde,
Metabolic response of AH13r rat tumours to cyclophosphamide as monitored by pO2 and pH semi-microelectrodes.
1992,
Pubmed
Jähde,
Nigericin enhances mafosfamide cytotoxicity at low extracellular pH.
1991,
Pubmed
Kim,
Radiosensitization of Meth-A fibrosarcoma in mice by Lonidamine.
1984,
Pubmed
Kim,
Potentiation of radiation effects on two murine tumors by lonidamine.
1986,
Pubmed
Kuin,
Potentiation of anti-cancer drug activity at low intratumoral pH induced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) and its analogue benzylguanidine (BG).
1999,
Pubmed
Lee,
Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma.
2013,
Pubmed
Liu,
Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells.
2015,
Pubmed
Loeber,
Cross-linking of the DNA repair protein Omicron6-alkylguanine DNA alkyltransferase to DNA in the presence of antitumor nitrogen mustards.
2008,
Pubmed
Lopez,
Intrapatient comparison of single-agent epirubicin with or without lonidamine in metastatic breast cancer.
1995,
Pubmed
Lyons,
Modification of intracellular pH and thermosensitivity.
1992,
Pubmed
Madiraju,
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.
2014,
Pubmed
Magno,
Double-blind randomized study of lonidamine and radiotherapy in head and neck cancer.
1994,
Pubmed
Magno,
Lonidamine and radiotherapy in head and neck cancers. A pilot study.
1984,
Pubmed
Mansi,
A phase II clinical and pharmacokinetic study of Lonidamine in patients with advanced breast cancer.
1991,
Pubmed
Marchiq,
Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin.
2015,
Pubmed
Mardor,
Noninvasive real-time monitoring of intracellular cancer cell metabolism and response to lonidamine treatment using diffusion weighted proton magnetic resonance spectroscopy.
2000,
Pubmed
Mathupala,
Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy.
2009,
Pubmed
McCoy,
The effect of blood flow modification on intra- and extracellular pH measured by 31P magnetic resonance spectroscopy in murine tumours.
1995,
Pubmed
Mendes-Mourāo,
The involvement of mitochondrial pyruvate transport in the pathways of gluconeogenesis from serine and alanine in isolated rat and mouse liver cells.
1975,
Pubmed
Nancolas,
The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters.
2016,
Pubmed
,
Xenbase
Nath,
Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin.
2015,
Pubmed
Nath,
Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan.
2015,
Pubmed
Nath,
Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice.
2016,
Pubmed
Nath,
(31) P and (1) H MRS of DB-1 melanoma xenografts: lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan.
2013,
Pubmed
Nisticò,
Weekly epirubicin plus lonidamine in advanced breast carcinoma.
1999,
Pubmed
Orecchioni,
The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells.
2015,
Pubmed
Pacini,
FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer. A multicentric randomised study. Final results.
2000,
Pubmed
Patra,
The pentose phosphate pathway and cancer.
2014,
Pubmed
Portalone,
Treatment of inoperable non-small cell lung carcinoma stage IIIb and IV with cisplatin, epidoxorubicin, vindesine and lonidamine: a phase II study.
1999,
Pubmed
Price,
Pharmacokinetics and toxicity of oral and intravenous lonidamine in dogs.
1996,
Pubmed
Price,
Effect of whole-body hyperthermia on the pharmacokinetics and toxicity of lonidamine in dogs.
1995,
Pubmed
Raghunand,
Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy.
1999,
Pubmed
Robins,
Phase I trial of lonidamine with whole body hyperthermia in advanced cancer.
1988,
Pubmed
Robustelli della Cuna,
Toxicity and clinical tolerance of lonidamine.
1991,
Pubmed
Roehrborn,
The development of lonidamine for benign prostatic hyperplasia and other indications.
2005,
Pubmed
Sadeghi,
Targeting prostate cancer cell metabolism: impact of hexokinase and CPT-1 enzymes.
2015,
Pubmed
Scarantino,
A prospective randomized comparison of radiation therapy plus lonidamine versus radiation therapy plus placebo as initial treatment of clinically localized but nonresectable nonsmall cell lung cancer.
1994,
Pubmed
Shestov,
(13)C MRS and LC-MS Flux Analysis of Tumor Intermediary Metabolism.
2016,
Pubmed
Shestov,
Bonded Cumomer Analysis of Human Melanoma Metabolism Monitored by 13C NMR Spectroscopy of Perfused Tumor Cells.
2016,
Pubmed
Shestov,
On the reliability of (13)C metabolic modeling with two-compartment neuronal-glial models.
2007,
Pubmed
Shestov,
Metabolic modeling of dynamic brain ¹³C NMR multiplet data: concepts and simulations with a two-compartment neuronal-glial model.
2012,
Pubmed
Silvestrini,
Lonidamine: an overview.
1991,
Pubmed
Skarsgard,
The cytotoxicity of melphalan and its relationship to pH, hypoxia and drug uptake.
1995,
Pubmed
Wheaton,
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis.
2014,
Pubmed
Wong,
Reduction of intracellular pH as a strategy to enhance the pH-dependent cytotoxic effects of melphalan for human breast cancer cells.
2005,
Pubmed
Yankovskaya,
Architecture of succinate dehydrogenase and reactive oxygen species generation.
2003,
Pubmed
Zhou,
Intracellular acidification of human melanoma xenografts by the respiratory inhibitor m-iodobenzylguanidine plus hyperglycemia: a 31P magnetic resonance spectroscopy study.
2000,
Pubmed
Zhou,
Enhancement of hyperglycemia-induced acidification of human melanoma xenografts with inhibitors of respiration and ion transport.
2001,
Pubmed