Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response

Kheshwant S. Gill1,2, Philana Fernandes1, Tracey R. O'Donovan1, Sharon L. McKenna1, Kishore K. Doddakula2, Derek G. Power1,3, Declan M. Soden1, Patrick F. Forde1
1Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland
2Cardiothoracic Surgery Department, Cork University Hospital, Cork, Ireland
3Department of Medical Oncology, Mercy University Hospital, Grenville Place, Cork, Ireland

Tài liệu tham khảo

Pace, 2001, The universal nature of biochemistry, Proc. Natl. Acad. Sci. U. S. A., 98, 805, 10.1073/pnas.98.3.805 Ebenhoh, 2001, Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems, Bull. Math. Biol., 63, 21, 10.1006/bulm.2000.0197 Melendez-Hevia, 1996, The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution, J. Mol. Evol., 43, 293, 10.1007/BF02338838 Keller, 2014, Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean, Mol. Syst. Biol., 10, 725, 10.1002/msb.20145228 Alfarouk, 2014, Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question, Oncoscience, 1, 777, 10.18632/oncoscience.109 Alfarouk, 2011, Tumor acidity as evolutionary spite, Cancer, 3, 408, 10.3390/cancers3010408 Gatenby, 2004, Why do cancers have high aerobic glycolysis?, Nat. Rev. Cancer, 4, 891, 10.1038/nrc1478 Kim, 2006, Cancer's molecular sweet tooth and the Warburg effect, Cancer Res., 66, 8927, 10.1158/0008-5472.CAN-06-1501 Warburg, 1956, On the origin of cancer cells, Science (New York, N.Y.), 123, 309, 10.1126/science.123.3191.309 Bertram, 2000, The molecular biology of cancer, Mol. Asp. Med., 21, 167, 10.1016/S0098-2997(00)00007-8 Grander, 1998, How do mutated oncogenes and tumor suppressor genes cause cancer?, Med. Oncol. (Northwood, Lond., Engl.), 15, 20, 10.1007/BF02787340 Ullah, 2006, The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism, J. Biol. Chem., 281, 9030, 10.1074/jbc.M511397200 Hu, 2012, K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis, Cell Res., 22, 399, 10.1038/cr.2011.145 Lu, 2012, Novel role of NOX in supporting aerobic glycolysis in cancer cells with mitochondrial dysfunction and as a potential target for cancer therapy, PLoS Biol., 10, 10.1371/journal.pbio.1001326 Wallace, 2012, Mitochondria and cancer, Nat. Rev. Cancer, 12, 685, 10.1038/nrc3365 de Souza, 2011, Defining the molecular basis of tumor metabolism: a continuing challenge since Warburg's discovery, Cell. Physiol. Biochem., 28, 771, 10.1159/000335792 Locasale, 2010, Altered metabolism in cancer, BMC Biol., 8, 88, 10.1186/1741-7007-8-88 Pfeiffer, 2001, Cooperation and competition in the evolution of ATP-producing pathways, Science (New York, N.Y.), 292, 504, 10.1126/science.1058079 Deberardinis, 2008, Brick by brick: metabolism and tumor cell growth, Curr. Opin. Genet. Dev., 18, 54, 10.1016/j.gde.2008.02.003 Backos, 2012, The role of glutathione in brain tumor drug resistance, Biochem. Pharmacol., 83, 1005, 10.1016/j.bcp.2011.11.016 Traverso, 2013, Role of glutathione in cancer progression and chemoresistance, Oxidative Med. Cell. Longev., 2013, 972913, 10.1155/2013/972913 Zhao, 2010, Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming, Oncogene, 29, 2962, 10.1038/onc.2010.67 Monteleone, 2013, Increased anaerobic metabolism is a distinctive signature in a colorectal cancer cellular model of resistance to antiepidermal growth factor receptor antibody, Proteomics, 13, 866, 10.1002/pmic.201200303 Rimpi, 2007, Metabolic enzymes regulated by the Myc oncogene are possible targets for chemotherapy or chemoprevention, Biochem. Soc. Trans., 35, 305, 10.1042/BST0350305 Elstrom, 2004, Akt stimulates aerobic glycolysis in cancer cells, Cancer Res., 64, 3892, 10.1158/0008-5472.CAN-03-2904 Csibi, 2011, Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors, BMC Biol., 9, 69, 10.1186/1741-7007-9-69 Duvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol. Cell, 39, 171, 10.1016/j.molcel.2010.06.022 Jiang, 2008, The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake, Am. J. Pathol., 172, 1748, 10.2353/ajpath.2008.070958 Palmieri, 2009, Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis, Mol. Cancer Res., 7, 1438, 10.1158/1541-7786.MCR-09-0234 Peng, 2008, Aberrant expression of the glycolytic enzymes aldolase B and type II hexokinase in hepatocellular carcinoma are predictive markers for advanced stage, early recurrence and poor prognosis, Oncol. Rep., 19, 1045 Pastorino, 2002, Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis, J. Biol. Chem., 277, 7610, 10.1074/jbc.M109950200 Rodriguez-Enriquez, 2009, Kinetics of transport and phosphorylation of glucose in cancer cells, J. Cell. Physiol., 221, 552, 10.1002/jcp.21885 Bhattacharya, 1959, Inhibition of liver hexokinase by dehydroascorbic acid and alloxan, Nature, 184, 1638, 10.1038/1841638b0 Del Bufalo, 1996, Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene, J. Clin. Invest., 98, 1165, 10.1172/JCI118900 Li, 2002, Mitochondrial targeting drug lonidamine triggered apoptosis in doxorubicin-resistant HepG2 cells, Life Sci., 71, 2729, 10.1016/S0024-3205(02)02103-3 Ravagnan, 1999, Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore, Oncogene, 18, 2537, 10.1038/sj.onc.1202625 Brawer, 2005, Lonidamine: basic science and rationale for treatment of prostatic proliferative disorders, Rev. Urol., 7, S21 Pelicano, 2006, Glycolysis inhibition for anticancer treatment, Oncogene, 25, 4633, 10.1038/sj.onc.1209597 Aft, 2002, Evaluation of 2-deoxy-d-glucose as a chemotherapeutic agent: mechanism of cell death, Br. J. Cancer, 87, 805, 10.1038/sj.bjc.6600547 Dell'Antone, 2009, Targets of 3-bromopyruvate, a new, energy depleting, anticancer agent, Med. Chem. (Shariqah (United Arab Emirates)), 5, 491, 10.2174/157340609790170551 Liu, 1997, Hypoglycemia-induced c-Jun phosphorylation is mediated by c-Jun N-terminal kinase 1 and Lyn kinase in drug-resistant human breast carcinoma MCF-7/ADR cells, J. Biol. Chem., 272, 11690, 10.1074/jbc.272.18.11690 Spitz, 2000, Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism?, Ann. N. Y. Acad. Sci., 899, 349, 10.1111/j.1749-6632.2000.tb06199.x Nomura, 1999, Mitochondrial phospholipid hydroperoxide glutathione peroxidase suppresses apoptosis mediated by a mitochondrial death pathway, J. Biol. Chem., 274, 29294, 10.1074/jbc.274.41.29294 Kaplan, 1990, Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism, Cancer Res., 50, 544 Mohanti, 1996, Improving cancer radiotherapy with 2-deoxy-d-glucose: phase I/II clinical trials on human cerebral gliomas, Int. J. Radiat. Oncol. Biol. Phys., 35, 103, 10.1016/S0360-3016(96)85017-6 Singh, 2005, Optimizing cancer radiotherapy with 2-deoxy-d-glucose dose escalation studies in patients with glioblastoma multiforme, Strahlenther. Onkol., 181, 507, 10.1007/s00066-005-1320-z Venkataramanaa, 2013, Protective effect on normal brain tissue during a combinational therapy of 2-deoxy-d-glucose and hypofractionated irradiation in malignant gliomas, Asian J. Neurosurg., 8, 9, 10.4103/1793-5482.110274 Zhong, 2009, The glycolytic inhibitor 2-deoxyglucose activates multiple prosurvival pathways through IGF1R, J. Biol. Chem., 284, 23225, 10.1074/jbc.M109.005280 Maher, 2007, Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-d-glucose, Mol. Cancer Ther., 6, 732, 10.1158/1535-7163.MCT-06-0407 Dwarakanath, 2009, Targeting glucose metabolism with 2-deoxy-d-glucose for improving cancer therapy, Future Oncol. (Lond. Engl.), 5, 581, 10.2217/fon.09.44 Maschek, 2004, 2-Deoxy-d-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo, Cancer Res., 64, 31, 10.1158/0008-5472.CAN-03-3294 Erecinska, 1995, The effect of pH on glycolysis and phosphofructokinase activity in cultured cells and synaptosomes, J. Neurochem., 65, 2765, 10.1046/j.1471-4159.1995.65062765.x Trivedi, 1966, Effect of pH on the kinetics of frog muscle phosphofructokinase, J. Biol. Chem., 241, 4110, 10.1016/S0021-9258(18)99819-4 Vora, 1985, Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy, Cancer Res., 45, 2993 Atsumi, 2002, High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers, Cancer Res., 62, 5881 Clem, 2008, Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth, Mol. Cancer Ther., 7, 110, 10.1158/1535-7163.MCT-07-0482 Vuyyuri, 2013, Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells, PLoS One, 8, 10.1371/journal.pone.0067081 Calvo, 2010, Potential role of sugar transporters in cancer and their relationship with anticancer therapy, Int. J. Endocrinol., 10.1155/2010/205357 Brophy, 2009, GLUT-1 expression and response to chemoradiotherapy in rectal cancer, Int. J. Cancer, 125, 2778, 10.1002/ijc.24693 Rastogi, 2007, Glut-1 antibodies induce growth arrest and apoptosis in human cancer cell lines, Cancer Lett., 257, 244, 10.1016/j.canlet.2007.07.021 Krzeslak, 2012, Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers, Pathol. Oncol. Res., 18, 721, 10.1007/s12253-012-9500-5 Macheda, 2005, Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer, J. Cell. Physiol., 202, 654, 10.1002/jcp.20166 Noguchi, 2000, Suppression of facilitative glucose transporter 1 mRNA can suppress tumor growth, Cancer Lett., 154, 175, 10.1016/S0304-3835(00)00392-X Flaig, 2010, A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer, Prostate, 70, 848, 10.1002/pros.21118 Chan, 2011, Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality, Sci. Transl. Med., 3, 10.1126/scitranslmed.3002394 Jiang, 2014, Nanoparticles of 2-deoxy-d-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment, Biomaterials, 35, 518, 10.1016/j.biomaterials.2013.09.094 Bonnet, 2007, A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth, Cancer Cell, 11, 37, 10.1016/j.ccr.2006.10.020 Sun, 2010, Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo, Breast Cancer Res. Treat., 120, 253, 10.1007/s10549-009-0435-9 Madhok, 2010, Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells, Br. J. Cancer, 102, 1746, 10.1038/sj.bjc.6605701 Cao, 2008, Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation, Prostate, 68, 1223, 10.1002/pros.20788 Wong, 2008, Dichloroacetate induces apoptosis in endometrial cancer cells, Gynecol. Oncol., 109, 394, 10.1016/j.ygyno.2008.01.038 Tas, 2001, Prognostic factors in pancreatic carcinoma: serum LDH levels predict survival in metastatic disease, Am. J. Clin. Oncol., 24, 547, 10.1097/00000421-200112000-00003 Armstrong, 2012, Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol., 30, 3402, 10.1200/JCO.2011.40.9631 Jin, 2013, Serum lactic dehydrogenase strongly predicts survival in metastatic nasopharyngeal carcinoma treated with palliative chemotherapy, Eur. J. Cancer (Oxf. Engl.: 1990), 49, 1619, 10.1016/j.ejca.2012.11.032 Koukourakis, 2003, Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis, Br. J. Cancer, 89, 877, 10.1038/sj.bjc.6601205 Le, 2010, Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression, Proc. Natl. Acad. Sci. U. S. A., 107, 2037, 10.1073/pnas.0914433107 Wang, 2012, LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis, Breast Cancer Res. Treat., 131, 791, 10.1007/s10549-011-1466-6 Zhou, 2010, Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol, Mol. Cancer, 9, 33, 10.1186/1476-4598-9-33 Fischer, 2007, Inhibitory effect of tumor cell-derived lactic acid on human T cells, Blood, 109, 3812, 10.1182/blood-2006-07-035972 Mendler, 2012, Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation, Int. J. Cancer, 131, 633, 10.1002/ijc.26410 Gottfried, 2006, Tumor-derived lactic acid modulates dendritic cell activation and antigen expression, Blood, 107, 2013, 10.1182/blood-2005-05-1795 Fischer, 2000, Acidic pH inhibits non-MHC-restricted killer cell functions, Clin. Immunol. (Orlando, Fla.), 96, 252, 10.1006/clim.2000.4904 Shime, 2008, Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway, J. Immunol. (Baltim. Md.: 1950), 180, 7175, 10.4049/jimmunol.180.11.7175 Yeluri, 2009, Cancer's craving for sugar: an opportunity for clinical exploitation, J. Cancer Res. Clin. Oncol., 135, 867, 10.1007/s00432-009-0590-8 Christofk, 2008, The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth, Nature, 452, 230, 10.1038/nature06734 Mazurek, 2005, Pyruvate kinase type M2 and its role in tumor growth and spreading, Semin. Cancer Biol., 15, 300, 10.1016/j.semcancer.2005.04.009 Fang, 2010, The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway, Cell, 143, 711, 10.1016/j.cell.2010.10.010 Marshall, 1991, Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance, J. Biol. Chem., 266, 4706, 10.1016/S0021-9258(19)67706-9 Vander Heiden, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science (New York, N.Y.), 324, 1029, 10.1126/science.1160809 Wang, 2010, Targeting mitochondrial glutaminase activity inhibits oncogenic transformation, Cancer Cell, 18, 207, 10.1016/j.ccr.2010.08.009 Porporato, 2011, Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review, Front. Pharmacol., 2, 49, 10.3389/fphar.2011.00049 Zhang, 2010, Antigen presentation by dendritic cells in tumors is disrupted by altered metabolism that involves pyruvate kinase M2 and its interaction with SOCS3, Cancer Res., 70, 89, 10.1158/0008-5472.CAN-09-2970 Frauwirth, 2002, The CD28 signaling pathway regulates glucose metabolism, Immunity, 16, 769, 10.1016/S1074-7613(02)00323-0 Matarese, 2004, The intricate interface between immune system and metabolism, Trends Immunol., 25, 193, 10.1016/j.it.2004.02.009 Oak, 1999, Activation of Fc epsilon RI inhibits the pyruvate kinase through direct interaction with the gamma-chain, Int. Arch. Allergy Immunol., 119, 95, 10.1159/000024183 Hatzivassiliou, 2005, ATP citrate lyase inhibition can suppress tumor cell growth, Cancer Cell, 8, 311, 10.1016/j.ccr.2005.09.008 Pizer, 2000, Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts, Cancer Res., 60, 213 Cheng, 2006, Design and synthesis of heterocyclic malonyl-CoA decarboxylase inhibitors, Bioorg. Med. Chem. Lett., 16, 695, 10.1016/j.bmcl.2005.10.020 Krauss, 2001, Signaling takes a breath—new quantitative perspectives on bioenergetics and signal transduction, Immunity, 15, 497, 10.1016/S1074-7613(01)00205-9 Buttgereit, 2000, Bioenergetics of immune functions: fundamental and therapeutic aspects, Immunol. Today, 21, 192, 10.1016/S0167-5699(00)01593-0 Crabtree, 1994, Signal transmission between the plasma membrane and nucleus of T lymphocytes, Annu. Rev. Biochem., 63, 1045, 10.1146/annurev.bi.63.070194.005145 Doughty, 2006, Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth, Blood, 107, 4458, 10.1182/blood-2005-12-4788 Fox, 2005, Fuel feeds function: energy metabolism and the T-cell response, Nat. Rev. Immunol., 5, 844, 10.1038/nri1710 Ouiddir, 1999, Hypoxia upregulates activity and expression of the glucose transporter GLUT1 in alveolar epithelial cells, Am. J. Respir. Cell Mol. Biol., 21, 710, 10.1165/ajrcmb.21.6.3751 Schuler, 1985, Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro, J. Exp. Med., 161, 526, 10.1084/jem.161.3.526 Winter, 1977, Oxygen and epidermal wound healing, Adv. Exp. Med. Biol., 94, 673, 10.1007/978-1-4684-8890-6_92 Sitkovsky, 2005, Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors, Nat. Rev. Immunol., 5, 712, 10.1038/nri1685 von Andrian, 2000, T-cell function and migration. Two sides of the same coin, N. Engl. J. Med., 343, 1020, 10.1056/NEJM200010053431407 Arnold, 1987, Wound healing: the effect of macrophage and tumour derived angiogenesis factors on skin graft vascularization, Br. J. Exp. Pathol., 68, 569 Helmlinger, 1997, Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation, Nat. Med., 3, 177, 10.1038/nm0297-177 Simmen, 1994, Analysis of pH, pO2 and pCO2 in drainage fluid allows for rapid detection of infectious complications during the follow-up period after abdominal surgery, Infection, 22, 386, 10.1007/BF01715494 Masopust, 2001, Preferential localization of effector memory cells in nonlymphoid tissue, Science (New York, N.Y.), 291, 2413, 10.1126/science.1058867 Roman, 2002, CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function, J. Exp. Med., 196, 957, 10.1084/jem.20021052 Borregaard, 1982, Energy metabolism of human neutrophils during phagocytosis, J. Clin. Invest., 70, 550, 10.1172/JCI110647 Cramer, 2003, HIF-1alpha is essential for myeloid cell-mediated inflammation, Cell, 112, 645, 10.1016/S0092-8674(03)00154-5 Krawczyk, 2010, Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation, Blood, 115, 4742, 10.1182/blood-2009-10-249540 Lacy-Hulbert, 2006, Designer macrophages: oxidative metabolism fuels inflammation repair, Cell Metab., 4, 7, 10.1016/j.cmet.2006.06.001 Vats, 2006, Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation, Cell Metab., 4, 13, 10.1016/j.cmet.2006.05.011 Healy, 2002, Glucose, but not glutamine, protects against spontaneous and anti-Fas antibody-induced apoptosis in human neutrophils, Clin. Sci. (Lond. Engl.: 1979), 103, 179, 10.1042/cs1030179 Savill, 1989, Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages, J. Clin. Invest., 83, 865, 10.1172/JCI113970 Pearce, 2010, Metabolism in T cell activation and differentiation, Curr. Opin. Immunol., 22, 314, 10.1016/j.coi.2010.01.018 Schmid, 2000, Bioenergetics of human peripheral blood mononuclear cell metabolism in quiescent, activated, and glucocorticoid-treated states, Biosci. Rep., 20, 289, 10.1023/A:1026445108136 Land, 1994, Protein turnover during metabolic arrest in turtle hepatocytes: role and energy dependence of proteolysis, Am. J. Phys., 266, C1028, 10.1152/ajpcell.1994.266.4.C1028 Princiotta, 2003, Quantitating protein synthesis, degradation, and endogenous antigen processing, Immunity, 18, 343, 10.1016/S1074-7613(03)00051-7 Lum, 2005, Autophagy in metazoans: cell survival in the land of plenty, Nat. Rev. Mol. Cell Biol., 6, 439, 10.1038/nrm1660 Yang, 2010, Eaten alive: a history of macroautophagy, Nat. Cell Biol., 12, 814, 10.1038/ncb0910-814 Rathmell, 2003, Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival, Mol. Cell. Biol., 23, 7315, 10.1128/MCB.23.20.7315-7328.2003 Maciver, 2008, Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival, J. Leukoc. Biol., 84, 949, 10.1189/jlb.0108024 Lu, 2002, Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis, J. Biol. Chem., 277, 23111, 10.1074/jbc.M202487200 Buttgereit, 1992, ConA induced changes in energy metabolism of rat thymocytes, Biosci. Rep., 12, 381, 10.1007/BF01121501 Marelli-Berg, 2012, Molecular mechanisms of metabolic reprogramming in proliferating cells: implications for T-cell-mediated immunity, Immunology, 136, 363, 10.1111/j.1365-2567.2012.03583.x Buttgereit, 1995, A hierarchy of ATP-consuming processes in mammalian cells, Biochem. J., 312, 163, 10.1042/bj3120163 Duchen, 1999, Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death, J. Physiol., 516, 1, 10.1111/j.1469-7793.1999.001aa.x Gatza, 2011, Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease, Sci. Transl. Med., 3, 10.1126/scitranslmed.3001975 Wahl, 2010, Characterization of the metabolic phenotype of chronically activated lymphocytes, Lupus, 19, 1492, 10.1177/0961203310373109 Michalek, 2011, Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets, J. Immunol. (Baltim. Md.: 1950), 186, 3299, 10.4049/jimmunol.1003613 Araki, 2009, mTOR regulates memory CD8 T-cell differentiation, Nature, 460, 108, 10.1038/nature08155 Hockel, 2001, Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects, J. Natl. Cancer Inst., 93, 266, 10.1093/jnci/93.4.266 Rathmell, 2000, In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability, Mol. Cell, 6, 683, 10.1016/S1097-2765(00)00066-6 van der Windt, 2012, Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development, Immunity, 36, 68, 10.1016/j.immuni.2011.12.007 Choi, 2009, Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: spare respiratory capacity and stochastic mitochondrial failure, J. Neurochem., 109, 1179, 10.1111/j.1471-4159.2009.06055.x Nicholls, 2009, Spare respiratory capacity, oxidative stress and excitotoxicity, Biochem. Soc. Trans., 37, 1385, 10.1042/BST0371385 Alves, 2006, The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells, Immunity, 24, 703, 10.1016/j.immuni.2006.03.018 Yamashita, 2008, Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene, J. Exp. Med., 205, 1109, 10.1084/jem.20072000 G. Bindea, B. Mlecnik, M. Tosolini, A. Kirilovsky, M. Waldner, Anna C. Obenauf, H. Angell, T. Fredriksen, L. Lafontaine, A. Berger, P. Bruneval, Wolf H. Fridman, C. Becker, F. Pagès, Michael R. Speicher, Z. Trajanoski, J. Galon, Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer, Immunity, 39 782-795. Biswas, 2010, Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm, Nat. Immunol., 11, 889, 10.1038/ni.1937 D. Hanahan, Lisa M. Coussens, Accessories to the crime: functions of cells recruited to the tumor microenvironment, Cancer Cell, 21 309-322. Erika L. Pearce, Edward J. Pearce, Metabolic pathways in immune cell activation and quiescence, Immunity, 38 633-643. Harding, 1992, CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones, Nature, 356, 607, 10.1038/356607a0 Wells, 2009, New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting, J. of Immunol. (Baltim. Md.: 1950), 182, 7331, 10.4049/jimmunol.0803917 Kuchroo, 1995, B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy, Cell, 80, 707, 10.1016/0092-8674(95)90349-6 Sperling, 1996, The complexities of T-cell co-stimulation: CD28 and beyond, Immunol. Rev., 153, 155, 10.1111/j.1600-065X.1996.tb00924.x Cairns, 2011, Regulation of cancer cell metabolism, Nat. Rev. Cancer, 11, 85, 10.1038/nrc2981 Patrick S. Ward, Craig B. Thompson, Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate, Cancer Cell, 21 297-308. Rathmell, 2003, Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma, Eur. J. Immunol., 33, 2223, 10.1002/eji.200324048 Frauwirth, 2004, Regulation of T lymphocyte metabolism, J. Immunol., 172, 4661, 10.4049/jimmunol.172.8.4661 Wieman, 2007, Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking, Mol. Biol. Cell, 18, 1437, 10.1091/mbc.E06-07-0593 Grumont, 2004, The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression, Immunity, 21, 19, 10.1016/j.immuni.2004.06.004 Wang, 2011, The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation, Immunity, 35, 871, 10.1016/j.immuni.2011.09.021 Wofford, 2008, IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival, Blood, 111, 2101, 10.1182/blood-2007-06-096297 Jacobs, 2008, Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways, J. Immunol., 180, 4476, 10.4049/jimmunol.180.7.4476 Fruman, 1999, Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha, Science (New York, N.Y.), 283, 393, 10.1126/science.283.5400.393 Delgoffe, 2009, mTOR: taking cues from the immune microenvironment, Immunology, 127, 459, 10.1111/j.1365-2567.2009.03125.x Cheng, 2014, mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity, Science (New York, N.Y.), 345, 10.1126/science.1250684 J.J. Howell, B.D. Manning, mTOR couples cellular nutrient sensing to organismal metabolic homeostasis, Trends Endocrinol. Metab., 22 94-102. Krawczyk, 2010, Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation, Blood, 115, 4742, 10.1182/blood-2009-10-249540 Brunn, 1997, Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin, Science (New York, N.Y.), 277, 99, 10.1126/science.277.5322.99 Dann, 2006, The amino acid sensitive TOR pathway from yeast to mammals, FEBS Lett., 580, 2821, 10.1016/j.febslet.2006.04.068 Howell, 2011, mTOR couples cellular nutrient sensing to organismal metabolic homeostasis, Trends Endocrinol. Metab., 22, 94, 10.1016/j.tem.2010.12.003 Kay, 1991, Inhibition of T and B lymphocyte proliferation by rapamycin, Immunology, 72, 544 Brown, 2007, The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes, Metab. Clin. Exp., 56, 1500, 10.1016/j.metabol.2007.06.016 Sipula, 2006, Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation, Metab. Clin. Exp., 55, 1637, 10.1016/j.metabol.2006.08.002 Powell, 1999, Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation, J. Immunol. (Baltim. Md.: 1950), 162, 2775 Zheng, 2007, A role for mammalian target of rapamycin in regulating T cell activation versus anergy, J. Immunol. (Baltim. Md.: 1950), 178, 2163, 10.4049/jimmunol.178.4.2163 Delgoffe, 2009, The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment, Immunity, 30, 832, 10.1016/j.immuni.2009.04.014 P.J. Siska, J.C. Rathmell, T cell metabolic fitness in antitumor immunity, Trends Immunol., 36 257-264. Finlay, 2010, Phosphoinositide 3-kinase and the mammalian target of rapamycin pathways control T cell migration, Ann. N. Y. Acad. Sci., 1183, 149, 10.1111/j.1749-6632.2009.05134.x Munk, 2011, Involvement of mTOR in CXCL12 mediated T cell signaling and migration, PLoS One, 6, 10.1371/journal.pone.0024667 Murooka, 2008, CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1, Blood, 111, 4892, 10.1182/blood-2007-11-125039 Hashimoto, 2008, Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells, Eur. J. cancer (Oxf. Engl. : 1990), 44, 1022, 10.1016/j.ejca.2008.02.043 Wang, 2008, CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway, Cancer Res., 68, 10367, 10.1158/0008-5472.CAN-08-2780 Sanchez-Alcazar, 1995, Down-regulation of tumor necrosis factor receptors by blockade of mitochondrial respiration, J. Biol. Chem., 270, 23944, 10.1074/jbc.270.41.23944 Karlsson, 1992, In vitro metabolic inhibition of the human lymphocyte: influence on the expression of interleukin-2 receptors, Immunol. Cell Biol., 70, 309, 10.1038/icb.1992.39 Choi, 2007, Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance, J. Clin. Invest., 117, 1995, 10.1172/JCI13579 Warne, 2003, Tumour necrosis factor alpha: a key regulator of adipose tissue mass, J. Endocrinol., 177, 351, 10.1677/joe.0.1770351 Matsuki, 2003, IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions, J. Exp. Med., 198, 877, 10.1084/jem.20030299 Wallenius, 2002, Interleukin-6-deficient mice develop mature-onset obesity, Nat. Med., 8, 75, 10.1038/nm0102-75 Bauer, 2004, Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand, FASEB J., 18, 1303, 10.1096/fj.03-1001fje Cousin, 1999, A role for preadipocytes as macrophage-like cells, FASEB J., 13, 305, 10.1096/fasebj.13.2.305 Wellen, 2003, Obesity-induced inflammatory changes in adipose tissue, J. Clin. Invest., 112, 1785, 10.1172/JCI20514 Takahashi, 2003, Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice, J. Biol. Chem., 278, 46654, 10.1074/jbc.M309895200 Ouchi, 2011, Adipokines in inflammation and metabolic disease, Nat. Rev. Immunol., 11, 85, 10.1038/nri2921 Feuerer, 2009, Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters, Nat. Med., 15, 930, 10.1038/nm.2002 Nishimura, 2009, CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity, Nat. Med., 15, 914, 10.1038/nm.1964 Rocha, 2008, Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity, Circ. Res., 103, 467, 10.1161/CIRCRESAHA.108.177105 Winer, 2009, Normalization of obesity-associated insulin resistance through immunotherapy, Nat. Med., 15, 921, 10.1038/nm.2001 Gajewski, 2012, Cancer immunotherapy, Mol. Oncol., 6, 242, 10.1016/j.molonc.2012.01.002 Mantovani, 2008, Tumour immunity: effector response to tumour and role of the microenvironment, Lancet (Lond. Engl.), 371, 771, 10.1016/S0140-6736(08)60241-X Quezada, 2011, Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication, Immunol. Rev., 241, 104, 10.1111/j.1600-065X.2011.01007.x Bodey, 2002, Spontaneous regression of neoplasms: new possibilities for immunotherapy, Expert. Opin. Biol. Ther., 2, 459, 10.1517/14712598.2.5.459 Kalialis, 2009, Spontaneous regression of metastases from melanoma: review of the literature, Melanoma Res., 19, 275, 10.1097/CMR.0b013e32832eabd5 Saleh, 2005, Direct evidence on the immune-mediated spontaneous regression of human cancer: an incentive for pharmaceutical companies to develop a novel anti-cancer vaccine, Curr. Pharm. Des., 11, 3531, 10.2174/138161205774414556 Jaakkola, 2001, Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation, Science (New York, N.Y.), 292, 468, 10.1126/science.1059796 Heddleston, 2010, Hypoxia inducible factors in cancer stem cells, Br. J. Cancer, 102, 789, 10.1038/sj.bjc.6605551 Hellwig-Burgel, 1999, Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1, Blood, 94, 1561, 10.1182/blood.V94.5.1561 Richard, 1999, p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1, J. Biol. Chem., 274, 32631, 10.1074/jbc.274.46.32631 Gatenby, 2007, Glycolysis in cancer: a potential target for therapy, Int. J. Biochem. Cell Biol., 39, 1358, 10.1016/j.biocel.2007.03.021 Chen, 2001, Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia, J. Biol. Chem., 276, 9519, 10.1074/jbc.M010144200 Kim, 2006, HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia, Cell Metab., 3, 177, 10.1016/j.cmet.2006.02.002 Sasabe, 2005, Mechanism of HIF-1alpha-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells, Cancer Sci., 96, 394, 10.1111/j.1349-7006.2005.00065.x Powis, 2004, Hypoxia inducible factor-1alpha as a cancer drug target, Mol. Cancer Ther., 3, 647, 10.1158/1535-7163.647.3.5 Richard, 2000, Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells, J. Biol. Chem., 275, 26765, 10.1016/S0021-9258(19)61441-9 Zhong, 2000, Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics, Cancer Res., 60, 1541 Dehne, 2009, HIF-1 in the inflammatory microenvironment, Exp. Cell Res., 315, 1791, 10.1016/j.yexcr.2009.03.019 Jantsch, 2008, Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function, Journal of immunology (Baltim. Md. : 1950), 180, 4697, 10.4049/jimmunol.180.7.4697 Panther, 2003, Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells, Blood, 101, 3985, 10.1182/blood-2002-07-2113 Thiel, 2005, Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury, PLoS Biol., 3, 10.1371/journal.pbio.0030174 Semenza, 2009, HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery, Curr. Pharm. Des., 15, 3839, 10.2174/138161209789649402 Zhang, 2008, Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth, Proc. Natl. Acad. Sci. U. S. A., 105, 19579, 10.1073/pnas.0809763105 Huh, 2011, Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity, Nature, 472, 486, 10.1038/nature09978 Onnis, 2009, Development of HIF-1 inhibitors for cancer therapy, J. Cell. Mol. Med., 13, 2780, 10.1111/j.1582-4934.2009.00876.x Welsh, 2004, Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha, Mol. Cancer Ther., 3, 233, 10.1158/1535-7163.233.3.3 Jeong, 2014, Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1alpha), in patients with refractory solid tumors, Cancer Chemother. Pharmacol., 73, 343, 10.1007/s00280-013-2362-z Nagaraja, 2010, A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer, Mol.Endocrinol. (Baltim. Md.), 24, 447, 10.1210/me.2009-0295 Liu, 2012, Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth, Mol. Pharm., 9, 2863, 10.1021/mp300193f Hughes, 2008, Evolutionary history of the UCP gene family: gene duplication and selection, BMC Evol. Biol., 8, 306, 10.1186/1471-2148-8-306 Skulachev, 1998, Uncoupling: new approaches to an old problem of bioenergetics, Biochim. Biophys. Acta, 1363, 100, 10.1016/S0005-2728(97)00091-1 Bouillaud, 2009, UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing, Biochim. Biophys. Acta, 1787, 377, 10.1016/j.bbabio.2009.01.003 Emre, 2010, Uncoupling protein UCP2: when mitochondrial activity meets immunity, FEBS Lett., 584, 1437, 10.1016/j.febslet.2010.03.014 Klingenberg, 1999, Structure and function of the uncoupling protein from brown adipose tissue, Biochim. Biophys. Acta, 1415, 271, 10.1016/S0005-2736(98)00232-6 Couplan, 2002, No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria, J. Biol. Chem., 277, 26268, 10.1074/jbc.M202535200 Mozo, 2006, Expression of UCP3 in CHO cells does not cause uncoupling, but controls mitochondrial activity in the presence of glucose, Biochem. J., 393, 431, 10.1042/BJ20050494 Arsenijevic, 2000, Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production, Nat. Genet., 26, 435, 10.1038/82565 Bai, 2005, Persistent nuclear factor-kappa B activation in Ucp2−/− mice leads to enhanced nitric oxide and inflammatory cytokine production, J. Biol. Chem., 280, 19062, 10.1074/jbc.M500566200 Rupprecht, 2012, Quantification of uncoupling protein 2 reveals its main expression in immune cells and selective up-regulation during T-cell proliferation, PLoS One, 7, 10.1371/journal.pone.0041406 Dando, 2013, UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells, Biochim. Biophys. Acta, 1833, 672, 10.1016/j.bbamcr.2012.10.028 Zhang, 2001, Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes, Cell, 105, 745, 10.1016/S0092-8674(01)00378-6 Ayyasamy, 2011, Cellular model of Warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin, PLoS One, 6, 10.1371/journal.pone.0024792 Brown, 2005, Effects of rottlerin on silica-exacerbated systemic autoimmune disease in New Zealand mixed mice, Am. J. Phys. Lung Cell. Mol. Phys., 289, L990 Shavell, 2012, Uncoupling oxidative phosphorylation with 2,4-dinitrophenol promotes development of the adhesion phenotype, Fertil. Steril., 97, 729, 10.1016/j.fertnstert.2011.12.009 Dalla Pozza, 2012, Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine, Biochim. Biophys. Acta, 1823, 1856, 10.1016/j.bbamcr.2012.06.007 Harrison, 2009, Rapamycin fed late in life extends lifespan in genetically heterogeneous mice, Nature, 460, 392, 10.1038/nature08221 Battaglia, 2006, Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients, J. Immunol. (Baltim. Md.: 1950), 177, 8338, 10.4049/jimmunol.177.12.8338 Kopf, 2007, Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells, Int. Immunopharmacol., 7, 1819, 10.1016/j.intimp.2007.08.027 Fielhaber, 2012, Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis, J. Immunol. (Baltim. Md.: 1950), 188, 4535, 10.4049/jimmunol.1003655 Watt, 2012, Impact of sirolimus and tacrolimus on mortality and graft loss in liver transplant recipients with or without hepatitis C virus: an analysis of the Scientific Registry of Transplant Recipients Database, Liver Transpl., 18, 1029, 10.1002/lt.23479 Ganapathy-Kanniappan, 2010, 3-Bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy, Curr. Pharm. Biotechnol., 11, 510, 10.2174/138920110791591427 Buijs, 2009, Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer, Investig. New Drugs, 27, 120, 10.1007/s10637-008-9145-0 Ko, 2004, Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP, Biochem. Biophys. Res. Commun., 324, 269, 10.1016/j.bbrc.2004.09.047 Feng, 2001, Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans, Dev. Cell, 1, 633, 10.1016/S1534-5807(01)00071-5 Rea, 2003, A metabolic model for life span determination in Caenorhabditis elegans, Dev. Cell, 5, 197, 10.1016/S1534-5807(03)00242-9 Hattori, 2006, Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells, Hypertension, 47, 1183, 10.1161/01.HYP.0000221429.94591.72 Kim, 2012, Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells, Biochem. Biophys. Res. Commun., 425, 866, 10.1016/j.bbrc.2012.07.165 Josse, 1998, Impairment of the mitochondrial electron chain transport prevents NF-kappa B activation by hydrogen peroxide, Free Radic. Biol. Med., 25, 104, 10.1016/S0891-5849(98)00057-4 Anedda, 2008, Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels, J. Endocrinol., 199, 33, 10.1677/JOE-08-0278 Shaw, 2004, The LKB1 tumor suppressor negatively regulates mTOR signaling, Cancer Cell, 6, 91, 10.1016/j.ccr.2004.06.007 Zakikhani, 2006, Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells, Cancer Res., 66, 10269, 10.1158/0008-5472.CAN-06-1500 Delmastro, 2011, Oxidative stress and redox modulation potential in type 1 diabetes, Clin. Dev. Immunol., 2011, 593863, 10.1155/2011/593863 Esrefoglu, 2012, Oxidative stress and benefits of antioxidant agents in acute and chronic hepatitis, Hepat. Mon., 12, 160, 10.5812/hepatmon.5090 Essa, 2012, Neuroprotective effect of natural products against Alzheimer's disease, Neurochem. Res., 37, 1829, 10.1007/s11064-012-0799-9 Fuchs-Tarlovsky, 2013, Role of antioxidants in cancer therapy, Nutrition (Burbank, Los Angel. County, Calif.), 29, 15, 10.1016/j.nut.2012.02.014 Zhu, 2012, Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence, Exp. Biol. Med. (Maywood, N.J.), 237, 474, 10.1258/ebm.2011.011358 Fernandez-Checa, 1998, Oxidative stress: role of mitochondria and protection by glutathione, BioFactors (Oxf. Engl.), 8, 7, 10.1002/biof.5520080102 Wang, 2012, Epigallocatechin-3-gallate inhibits expression of receptors for T cell regulatory cytokines and their downstream signaling in mouse CD4+ T cells, J. Nutr., 142, 566, 10.3945/jn.111.154419 Wang, 2012, Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T-cell subsets, Am. J. Pathol., 180, 221, 10.1016/j.ajpath.2011.09.007 Checker, 2012, Potent anti-inflammatory activity of ursolic acid, a triterpenoid antioxidant, is mediated through suppression of NF-kappaB, AP-1 and NF-AT, PLoS One, 7, 10.1371/journal.pone.0031318 Guo, 2012, Nutritional supplement therapy improves oxidative stress, immune response, pulmonary function, and quality of life in allergic asthma patients: an open-label pilot study, Altern. Med. Rev., 17, 42 Tse, 2004, Mechanistic analysis of the immunomodulatory effects of a catalytic antioxidant on antigen-presenting cells: implication for their use in targeting oxidation-reduction reactions in innate immunity, Free Radic. Biol. Med., 36, 233, 10.1016/j.freeradbiomed.2003.10.029 Sharma, 2012, Antioxidant alpha-tocopherol checks lymphoma promotion via regulation of expression of protein kinase C-alpha and c-Myc genes and glycolytic metabolism, Leuk. Lymphoma, 53, 1203, 10.3109/10428194.2011.637213 Delmastro, 2012, Modulation of redox balance leaves murine diabetogenic TH1 T cells “LAG-3-ing” behind, Diabetes, 61, 1760, 10.2337/db11-1591 Sklavos, 2008, Redox modulation inhibits CD8 T cell effector function, Free Radic. Biol. Med., 45, 1477, 10.1016/j.freeradbiomed.2008.08.023 Rabbani, 2009, Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor, Free Radic. Biol. Med., 47, 992, 10.1016/j.freeradbiomed.2009.07.001 Koppers-Lalic, 2013, Virus-modified exosomes for targeted RNA delivery; a new approach in nanomedicine, Adv. Drug Deliv. Rev., 65, 348, 10.1016/j.addr.2012.07.006 Moser, 2011, Influenza virosomes as a vaccine adjuvant and carrier system, Expert Rev. Vaccines, 10, 437, 10.1586/erv.11.15 Schaap, 2012, Effect of envelope proteins on the mechanical properties of influenza virus, J. Biol. Chem., 287, 41078, 10.1074/jbc.M112.412726 Zamparo, 2011, Immunogenicity and effectiveness of virosomal adjuvanted vaccines against influenza: a brief review of their utility in the elderly population, J. Prev. Med. Hyg., 52, 116 Cinti, 2011, Newly engineered magnetic erythrocytes for sustained and targeted delivery of anti-cancer therapeutic compounds, PLoS One, 6, 10.1371/journal.pone.0017132 Kaneda, 2012, Virosome: a novel vector to enable multi-modal strategies for cancer therapy, Adv. Drug Deliv. Rev., 64, 730, 10.1016/j.addr.2011.03.007 Yoo, 2011, Bio-inspired, bioengineered and biomimetic drug delivery carriers, Nat. Rev. Drug Discov., 10, 521, 10.1038/nrd3499 Kay, 2001, Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics, Nat. Med., 7, 33, 10.1038/83324 Zhou, 1999, RNA melanoma vaccine: induction of antitumor immunity by human glycoprotein 100 mRNA immunization, Hum. Gene Ther., 10, 2719, 10.1089/10430349950016762 Kamimura, 2011, Advances in gene delivery systems, Pharm. Med., 25, 293, 10.1007/BF03256872 Nayerossadat, 2012, Viral and nonviral delivery systems for gene delivery, Adv. Biol. Res., 1, 27 Souza, 2005, Recombinant viruses as vaccines against viral diseases, Braz. J. Med. Biol. Res., 38, 509, 10.1590/S0100-879X2005000400004 Morille, 2008, Progress in developing cationic vectors for non-viral systemic gene therapy against cancer, Biomaterials, 29, 3477, 10.1016/j.biomaterials.2008.04.036 Felgner, 1987, Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure, Proc. Natl. Acad. Sci. U. S. A., 84, 7413, 10.1073/pnas.84.21.7413 Nabel, 1993, Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans, Proc. Natl. Acad. Sci. U. S. A., 90, 11307, 10.1073/pnas.90.23.11307 Wheeler, 1996, A novel cationic lipid greatly enhances plasmid DNA delivery and expression in mouse lung, Proc. Natl. Acad. Sci. U. S. A., 93, 11454, 10.1073/pnas.93.21.11454 Yoshida, 2004, Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes, Hum. Gene Ther., 15, 77, 10.1089/10430340460732472 Allen, 2004, Drug delivery systems: entering the mainstream, Science (New York, N.Y.), 303, 1818, 10.1126/science.1095833 Wang, 2008, Application of nanotechnology in cancer therapy and imaging, CA Cancer J. Clin., 58, 97, 10.3322/CA.2007.0003 Muthu, 2014, Nanotheranostics - application and further development of nanomedicine strategies for advanced theranostics, Theranostics, 4, 660, 10.7150/thno.8698 Pavot, 2014, Poly(lactic acid) and poly(lactic-co-glycolic acid) particles as versatile carrier platforms for vaccine delivery, Nanomedicine (Lond. Engl.), 9, 2703, 10.2217/nnm.14.156 Abu Samah, 2013, Enhanced in vitro transdermal delivery of caffeine using a temperature- and pH-sensitive nanogel, poly(NIPAM-co-AAc), Int. J. Pharm., 453, 630, 10.1016/j.ijpharm.2013.05.042 Han, 2009, Enhanced percolation and gene expression in tumor hypoxia by PEGylated polyplex micelles, Mol. Ther., 17, 1404, 10.1038/mt.2009.119 Kim, 2009, In vivo evaluation of doxorubicin-loaded polymeric micelles targeting folate receptors and early endosomal pH in drug-resistant ovarian cancer, Mol. Pharm., 6, 1353, 10.1021/mp900021q Hanai, 2004, Potential of atelocollagen-mediated systemic antisense therapeutics for inflammatory disease, Hum. Gene Ther., 15, 263, 10.1089/104303404322886110 Takeshita, 2005, Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo, Proc. Natl. Acad. Sci. U. S. A., 102, 12177, 10.1073/pnas.0501753102 Kushibiki, 2004, Suppression of tumor metastasis by NK4 plasmid DNA released from cationized gelatin, Gene Ther., 11, 1205, 10.1038/sj.gt.3302285 Erbacher, 1998, Chitosan-based vector/DNA complexes for gene delivery: biophysical characteristics and transfection ability, Pharm. Res., 15, 1332, 10.1023/A:1011981000671 Howard, 2006, RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system, Mol. Ther., 14, 476, 10.1016/j.ymthe.2006.04.010 Boussif, 1995, A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine, Proc. Natl. Acad. Sci. U. S. A., 92, 7297, 10.1073/pnas.92.16.7297 Alshamsan, 2010, The induction of tumor apoptosis in B16 melanoma following STAT3 siRNA delivery with a lipid-substituted polyethylenimine, Biomaterials, 31, 1420, 10.1016/j.biomaterials.2009.11.003 Wang, 2006, Combination of adsorption by porous CaCO3 microparticles and encapsulation by polyelectrolyte multilayer films for sustained drug delivery, Int. J. Pharm., 308, 160, 10.1016/j.ijpharm.2005.11.004 Wolff, 1990, Direct gene transfer into mouse muscle in vivo, Science (New York, N.Y.), 247, 1465, 10.1126/science.1690918 Wolff, 2005, The mechanism of naked DNA uptake and expression, Adv. Genet., 54, 3 Neumann, 1982, Gene transfer into mouse lyoma cells by electroporation in high electric fields, EMBO J., 1, 841, 10.1002/j.1460-2075.1982.tb01257.x Edd, 2006, In vivo results of a new focal tissue ablation technique: irreversible electroporation, IEEE Trans. Biomed. Eng., 53, 1409, 10.1109/TBME.2006.873745 Rubinsky, 2007, Irreversible electroporation: a new ablation modality–clinical implications, Technol. Cancer Res. Treat., 6, 37, 10.1177/153303460700600106 Levine, 2012, Calcium and phosphatidylserine inhibit lipid electropore formation and reduce pore lifetime, J. Membr. Biol., 245, 599, 10.1007/s00232-012-9471-1 Pucihar, 2006, Numerical determination of transmembrane voltage induced on irregularly shaped cells, Ann. Biomed. Eng., 34, 642, 10.1007/s10439-005-9076-2 J. Teissié, M.P. Rols, An experimental evaluation of the critical potential difference inducing cell membrane electropermeabilization, Biophys. J., 65 409-413. Pucihar, 2007, Electropermeabilization of dense cell suspensions, Eur. Biophys. J., 36, 173, 10.1007/s00249-006-0115-1 Gehl, 2005, [Investigational treatment of cancer using electrochemotherapy, electrochemoimmunotherapy and electro-gene transfer], Ugeskr. Laeger, 167, 3156 Liu, 2002, A syringe electrode device for simultaneous injection of DNA and electrotransfer, Mol. Ther., 5, 323, 10.1006/mthe.2002.0540 Edhemovic, 2011, Electrochemotherapy: a new technological approach in treatment of metastases in the liver, Technol. Cancer Res. Treat., 10, 475, 10.7785/tcrt.2012.500224 Golzio, 2004, In vitro and in vivo electric field-mediated permeabilization, gene transfer, and expression, Methods (San Diego, Calif.), 33, 126, 10.1016/j.ymeth.2003.11.003 Zhu, 2010, IL-12 and IL-27 sequential gene therapy via intramuscular electroporation delivery for eliminating distal aggressive tumors, J. Immunol. (Baltim. Md.: 1950), 184, 2348, 10.4049/jimmunol.0902371 Matthiessen, 2012, Electrochemotherapy for large cutaneous recurrence of breast cancer: a phase II clinical trial, Acta Oncol. (Stockholm, Sweden), 51, 713, 10.3109/0284186X.2012.685524 Kyte, 2006, Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA, Cancer Gene Ther., 13, 905, 10.1038/sj.cgt.7700961 Daud, 2008, Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol., 26, 5896, 10.1200/JCO.2007.15.6794 Kassan, 1996, Physical enhancement of dermatologic drug delivery: iontophoresis and phonophoresis, J. Am. Acad. Dermatol., 34, 657, 10.1016/S0190-9622(96)80069-7 Taniyama, 2002, Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle, Gene Ther., 9, 372, 10.1038/sj.gt.3301678 Casey, 2010, Sonoporation mediated immunogene therapy of solid tumors, Ultrasound Med. Biol., 36, 430, 10.1016/j.ultrasmedbio.2009.11.005 Hayashi, 2009, Effect of sonoporation on cationic liposome-mediated IFNbeta gene therapy for metastatic hepatic tumors of murine colon cancer, Cancer Gene Ther., 16, 638, 10.1038/cgt.2008.1 Iwanaga, 2007, Local delivery system of cytotoxic agents to tumors by focused sonoporation, Cancer Gene Ther., 14, 354, 10.1038/sj.cgt.7701026 Lopez, 2011, Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate, Biomaterials, 32, 933, 10.1016/j.biomaterials.2010.09.060 Polat, 2011, Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends, J. Control. Release, 152, 330, 10.1016/j.jconrel.2011.01.006 Budker, 1998, The efficient expression of intravascularly delivered DNA in rat muscle, Gene Ther., 5, 272, 10.1038/sj.gt.3300572 Zhang, 1999, High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA, Hum. Gene Ther., 10, 1735, 10.1089/10430349950017734 Liu, 1999, Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA, Gene Ther., 6, 1258, 10.1038/sj.gt.3300947 Suda, 2007, Hydrodynamic gene delivery: its principles and applications, Mol. Ther., 15, 2063, 10.1038/sj.mt.6300314 Yazawa, 2006, Hydrodynamics-based gene delivery of naked DNA encoding fetal liver kinase-1 gene effectively suppresses the growth of pre-existing tumors, Cancer Gene Ther., 13, 993, 10.1038/sj.cgt.7700970 Neal, 2007, Hydrodynamic limb vein delivery of a xenogeneic DNA cancer vaccine effectively induces antitumor immunity, Mol. Ther., 15, 422, 10.1038/sj.mt.6300046 Mozzillo, 2015, Assessing a novel immuno-oncology-based combination therapy: ipilimumab plus electrochemotherapy, Oncoimmunology, 4, 10.1080/2162402X.2015.1008842