Tumor metabolism, cancer cell transporters, and microenvironmental resistance

References

• Alfarouk KO, Shayoub MEAA, Muddathir AK, et al Evolution of tumor metabolism might reflect carcinogenesis as a reverse evolution process (dismantling of multicellularity). Cancers (Basel) 2011;3:3002–17
   PubMedGoogle Scholar
• Alfarouk KO, Verduzco D, Rauch C, et al Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Oncoscience 2014;1:777–802
   PubMedGoogle Scholar
• Moldovan L, Mythreye K, Goldschmidt-Clermont PJ, Satterwhite LL. Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1. Cardiovasc Res 2006;71:236–46
   PubMed Web of Science ®Google Scholar
• Kim J-S, Huang TY, Bokoch GM. Reactive oxygen species regulate a slingshot-cofilin activation pathway. Mol Biol Cell 2009;20:2650–60
   PubMed Web of Science ®Google Scholar
• Luanpitpong S, Talbott SJ, Rojanasakul Y, et al Regulation of lung cancer cell migration and invasion by reactive oxygen species and caveolin-1. J Biol Chem 2010;285:38832–40
   PubMed Web of Science ®Google Scholar
• Hurd TR, DeGennaro M, Lehmann R. Redox regulation of cell migration and adhesion. Trends Cell Biol 2012;22:107–15
   PubMed Web of Science ®Google Scholar
• Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004;4:891–9
   PubMed Web of Science ®Google Scholar
• Kelloff GJ, Hoffman JM, Johnson B, et al Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res 2005;11:2785–808
   PubMed Web of Science ®Google Scholar
• Nijsten MWN, van Dam GM. Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate. Med Hypotheses 2009;73:48–51
   PubMed Web of Science ®Google Scholar
• Bailey KM, Wojtkowiak JW, Hashim AI, Gillies RJ. Targeting the metabolic microenvironment of tumors. Adv Pharmacol 2012;65:63–107
   PubMedGoogle Scholar
• Silva AS, Yunes JA, Gillies RJ, et al The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. Cancer Res 2009;69:2677–84
   PubMed Web of Science ®Google Scholar
• Martin NK, Robey IF, Gaffney EA, et al Predicting the safety and efficacy of buffer therapy to raise tumour pH: an integrative modelling study. Br J Cancer 2012;106:1280–7
   PubMed Web of Science ®Google Scholar
• Putignani L, Raffa S, Pescosolido R, et al Mitochondrion Preliminary evidences on mitochondrial injury and impaired oxidative metabolism in breast cancer. Mitochondrion 2012;12:363–9
   PubMed Web of Science ®Google Scholar
• Cza as rnecka AM, Gammazza AM, Felice VD, et al Cancer as a “mitochondriopathy”. J Cancer Mol 2007;3:71–9
   Google Scholar
• Czarnecka AM, Czarnecki JS, Kukwa W, et al Molecular oncology focus – is carcinogenesis a “mitochondriopathy”? J Biomed Sci 2010;17:31
   PubMed Web of Science ®Google Scholar
• Higuchi M. Regulation of mitochondrial DNA content and cancer. Mitochondrion 2007;7:53–7
   PubMed Web of Science ®Google Scholar
• Wen S, Zhang F, Feng S. Decreased copy number of mitochondrial DNA: a potential diagnostic criterion for gastric cancer. Oncol Lett 2013;6:1098–102
   PubMed Web of Science ®Google Scholar
• Thyagarajan B, Wang R, Nelson H, et al Mitochondrial DNA copy number is associated with breast cancer risk. PLoS One 2013;8:e65968
   PubMed Web of Science ®Google Scholar
• Cui H, Huang P, Wang Z, et al Association of decreased mitochondrial DNA content with the progression of colorectal cancer. BMC Cancer 2013;13:110
   PubMed Web of Science ®Google Scholar
• Garber K. Energy boost: the Warburg effect returns in a new theory of cancer. J Natl Cancer Inst 2004;96:1805–6
   PubMedGoogle Scholar
• Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029–33
   PubMed Web of Science ®Google Scholar
• DeBerardinis RJ, Thompson CB. Cellular metabolism and disease: what do metabolic outliers teach us? Cell 2012;148:1132–44
   PubMed Web of Science ®Google Scholar
• Reed JC, Jurgensmeier JM, Matsuyama S. Bcl-2 family proteins and mitochondria. Biochim Biophys Acta 1998;1366:127–37
   PubMed Web of Science ®Google Scholar
• Green DR, Reed JC. Mitochondria and apoptosis. Science 1998;281:1309–12
   PubMed Web of Science ®Google Scholar
• Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet 2009;43:95–118
   PubMed Web of Science ®Google Scholar
• Rehman J, Zhang HJ, Toth PT, et al Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J 2012;26:2175–86
   PubMed Web of Science ®Google Scholar
• Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 2010;11:872–84
   PubMed Web of Science ®Google Scholar
• Chen H, Chan DC. Mitochondrial dynamics – fusion, fission, movement, and mitophagy – in neurodegenerative diseases. Hum Mol Genet 2009;18:R169–76
   PubMed Web of Science ®Google Scholar
• Reshkin SJ, Bellizzi A, Caldeira S, et al Na+/H + exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 2000;14:2185–97
   PubMed Web of Science ®Google Scholar
• Gatenby RA, Smallbone K, Maini PK, et al Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer 2007;97:646–53
   PubMed Web of Science ®Google Scholar
• Tse CM, Ma AI, Yang VW, et al Molecular cloning and expression of a cDNA encoding the rabbit ileal villus cell basolateral membrane Na+/H + exchanger. EMBO J 1991;10:1957–67
   PubMed Web of Science ®Google Scholar
• Tse CM, Levine SA, Yun CH, et al Cloning and expression of a rabbit cDNA encoding a serum-activated ethylisopropylamiloride-resistant epithelial Na+/H + exchanger isoform (NHE-2). J Biol Chem 1993;268:11917–24
   PubMed Web of Science ®Google Scholar
• Fliegel L, Dyck JR, Wang H, et al Cloning and analysis of the human myocardial Na+/H + exchanger. Mol Cell Biochem 1993;125:137–43
   PubMed Web of Science ®Google Scholar
• Denker SP, Huang DC, Orlowski J, et al Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Mol Cell 2000;6:1425–36
   PubMed Web of Science ®Google Scholar
• Torres-López JE, Guzmán-Priego CG, Rocha-González HI, Granados-Soto V. Role of NHE1 in nociception. Pain Res Treat 2013;2013:217864
   PubMedGoogle Scholar
• Fliegel L. The Na+/H + exchanger isoform 1. Int J Biochem Cell Biol 2005;37:33–7
   PubMed Web of Science ®Google Scholar
• Provost JJ, Wallert Ma. Inside out: targeting NHE1 as an intracellular and extracellular regulator of cancer progression. Chem Biol Drug Des 2013;81:85–101
   PubMed Web of Science ®Google Scholar
• Schwab A. Function and spatial distribution of ion channels and transporters in cell migration. Am J Physiol Renal Physiol 2001;280:F739–47
   PubMed Web of Science ®Google Scholar
• Reshkin SJ, Cardone RA, Harguindey S. Na+-H + exchanger, pH regulation and cancer. Recent Pat Anticancer Drug Discov 2013;8:85–99
   PubMed Web of Science ®Google Scholar
• Raghunand N, He X, van Sluis R, et al Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer 1999;80:1005–11
   PubMed Web of Science ®Google Scholar
• Raghunand N, Mahoney BP, Gillies RJ. Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol 2003;66:1219–29
   PubMed Web of Science ®Google Scholar
• Mahoney BP, Raghunand N, Baggett B, Gillies RJ. Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem Pharmacol 2003;66:1207–18
   PubMed Web of Science ®Google Scholar
• Harguindey S, Arranz JL, Polo Orozco JD, et al Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs-an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. J Transl Med 2013;11:282
   PubMed Web of Science ®Google Scholar
• Harguindey S, Orive G, Luis Pedraz J, et al The role of pH dynamics and the Na+/H + antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin-one single nature. Biochim Biophys Acta 2005;1756:1–24
   PubMed Web of Science ®Google Scholar
• Harguindey S, Arranz JL, Wahl ML, et al Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res 2009;29:2127–36
   PubMed Web of Science ®Google Scholar
• Pinheiro C, Longatto-Filho A, Azevedo-Silva J, et al Role of monocarboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr 2012;44:127–39
   PubMed Web of Science ®Google Scholar
• Adijanto J, Philp NJ. The SLC16A family of monocarboxylate transporters (MCTs)-physiology and function in cellular metabolism, pH homeostasis, and fluid transport. Curr Top Membr 2012;70:275–311
   PubMed Web of Science ®Google Scholar
• Poole RC, Halestrap AP. Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol 1993;264:C761–82
   PubMed Web of Science ®Google Scholar
• Garcia CK, Goldstein JL, Pathak RK, et al Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 1994;76:865–73
   PubMed Web of Science ®Google Scholar
• Alfarouk KO, Muddathir AK, Shayoub MEA. Tumor acidity as evolutionary spite. Cancers (Basel) 2011;3:408–14
   PubMedGoogle Scholar
• Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol (Lond) 2009;587:5591–600
   Google Scholar
• Hirschhaeuser F, Sattler UGA, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res 2011;71:6921–5
   PubMed Web of Science ®Google Scholar
• Dhup S, Dadhich RK, Porporato PE, Sonveaux P. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 2012;18:1319–30
   PubMed Web of Science ®Google Scholar
• Jóhannsson E, Nagelhus EA, McCullagh KJ, et al Cellular and subcellular expression of the monocarboxylate transporter MCT1 in rat heart. A high-resolution immunogold analysis. Circ Res 1997;80:400–7
   PubMed Web of Science ®Google Scholar
• Gray MW, Burger G, Lang BF. Mitochondrial evolution. Science 1999;283:1476–81
   PubMed Web of Science ®Google Scholar
• Andersson SGE, Karlberg O, Canbäck B, Kurland CG. On the origin of mitochondria: a genomics perspective. Philos Trans R Soc Lond B Biol Sci 2003;358:165–77
   PubMed Web of Science ®Google Scholar
• Gray MW, Burger G, Lang BF. The origin and early evolution of mitochondria. Genome Biol 2001;2:reviews1018.1–reviews1018.5
   Web of Science ®Google Scholar
• Hashimoto T, Hussien R, Brooks GA. Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am J Physiol Endocrinol Metab 2006;290:E1237–44
   PubMed Web of Science ®Google Scholar
• Gabaldón T, Snel B, van Zimmeren F, et al Origin and evolution of the peroxisomal proteome. Biol Direct 2006;1:8
   PubMed Web of Science ®Google Scholar
• McClelland GB, Khanna S, González GF, et al Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system? Biochem Biophys Res Commun 2003;304:130–5
   PubMed Web of Science ®Google Scholar
• Zha S, Ferdinandusse S, Hicks JL, et al Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostate cancer. Prostate 2005;63:316–23
   PubMed Web of Science ®Google Scholar
• Izumi H, Torigoe T, Ishiguchi H, et al Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 2003;29:541–9
   PubMed Web of Science ®Google Scholar
• De Saedeleer CJ, Porporato PE, Copetti T, et al Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. Oncogene 2014;33:4060–8
   PubMed Web of Science ®Google Scholar
• Zhao Z, Wu M-S, Zou C, et al Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway. Cancer Lett 2014;342:150–8
   PubMed Web of Science ®Google Scholar
• Pinheiro C, Sousa B, Albergaria A, et al GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol 2011;26:1279–86
   PubMed Web of Science ®Google Scholar
• Curry JM, Tuluc M, Whitaker-Menezes D, et al Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle 2013;12:1371–84
   PubMed Web of Science ®Google Scholar
• Shih H-J, Chen H-H, Chen Y-A, et al Targeting MCT-1 oncogene inhibits Shc pathway and xenograft tumorigenicity. Oncotarget 2012;3:1401–15
   PubMed Web of Science ®Google Scholar
• Birsoy K, Wang T, Possemato R, et al MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat Genet 2013;45:104–8
   PubMed Web of Science ®Google Scholar
• Sonveaux P, Copetti T, De Saedeleer CJ, et al Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One 2012;7:e33418
   PubMed Web of Science ®Google Scholar
• Ohsumi Y, Anraku Y. Active transport of basic amino acids driven by a proton motive force in vacuolar membrane vesicles of Saccharomyces cerevisiae. J Biol Chem 1981;256:2079–82
   PubMed Web of Science ®Google Scholar
• Nelson N. Evolution of organellar proton-ATPases. Biochim Biophys Acta 1992;1100:109–24
   PubMed Web of Science ®Google Scholar
• Nelson N. Organellar proton-ATPases. Curr Opin Cell Biol 1992;4:654–60
   PubMedGoogle Scholar
• Nishi T, Forgac M. The vacuolar (H+)-ATPases-nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 2002;3:94–103
   PubMed Web of Science ®Google Scholar
• Merzendorfer H, Gräf R, Huss M, et al Regulation of proton-translocating V-ATPases. J Exp Biol 1997;200:225–35
   PubMed Web of Science ®Google Scholar
• Fais S, De Milito A, You H, Qin W. Targeting vacuolar H+-ATPases as a new strategy against cancer. Cancer Res 2007;67:10627–30
   PubMed Web of Science ®Google Scholar
• Sennoune SR, Bakunts K, Martínez GM, et al Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am J Physiol Cell Physiol 2004;286:C1443–52
   PubMed Web of Science ®Google Scholar
• Martínez-Zaguilán R, Raghunand N, Lynch RM, et al pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. Biochem Pharmacol 1999;57:1037–46
   PubMed Web of Science ®Google Scholar
• Lu Q, Lu S, Huang L, et al The expression of V-ATPase is associated with drug resistance and pathology of non-small-cell lung cancer. Diagn Pathol 2013;8:145
   PubMed Web of Science ®Google Scholar
• Wang B-Y, Zhang J, Wang J-L, et al Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. J Exp Clin Cancer Res 2015;34:85
   PubMed Web of Science ®Google Scholar
• Spugnini EP, Buglioni S, Carocci F, et al High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med 2014;12:225
   PubMed Web of Science ®Google Scholar
• Ferrari S, Perut F, Fagioli F, et al Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J Transl Med 2013;11:268
   PubMed Web of Science ®Google Scholar
• Spugnini EP, Baldi A, Buglioni S, et al Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med 2011;9:221
   PubMed Web of Science ®Google Scholar
• Lugini L, Federici C, Borghi M, et al Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect. J Enzyme Inhib Med Chem 2015;30:1–8
   PubMed Web of Science ®Google Scholar
• Papagerakis S, Bellile E, Peterson LA, et al Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma. Cancer Prev Res (Phila) 2014;7:1258–69
   PubMed Web of Science ®Google Scholar
• Opavský R, Pastoreková S, Zelník V, et al Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 1996;33:480–7
   PubMed Web of Science ®Google Scholar
• Chen J, Röcken C, Hoffmann J, et al Expression of carbonic anhydrase 9 at the invasion front of gastric cancers. Gut 2005;54:920–7
   PubMed Web of Science ®Google Scholar
• Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 2007;26:299–310
   PubMed Web of Science ®Google Scholar
• Robertson N, Potter C, Harris AL. Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res 2004;64:6160–5
   PubMed Web of Science ®Google Scholar
• Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 2008;7:168–81
   PubMed Web of Science ®Google Scholar
• Svastova E, Witarski W, Csaderova L, et al Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem 2012;287:3392–402
   PubMed Web of Science ®Google Scholar
• Ivanov S, Liao S-Y, Ivanova A, et al Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 2001;158:905–19
   PubMed Web of Science ®Google Scholar
• Yang J-S, Lin C-W, Chuang C-Y, et al Carbonic anhydrase IX overexpression regulates the migration and progression in oral squamous cell carcinoma. Tumour Biol 2015;36:9517–24
   PubMed Web of Science ®Google Scholar
• Lou Y, McDonald PC, Oloumi A, et al Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 2011;71:3364–76
   PubMed Web of Science ®Google Scholar
• McDonald PC, Winum J-Y, Supuran CT, Dedhar S. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 2012;3:84–97
   PubMed Web of Science ®Google Scholar
• Tan EY, Yan M, Campo L, et al The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br J Cancer 2009;100:405–11
   PubMed Web of Science ®Google Scholar
• Said HM, Supuran CT, Hageman C, et al Modulation of carbonic anhydrase 9 (CA9) in human brain cancer. Curr Pharm Des 2010;16:3288–99
   PubMed Web of Science ®Google Scholar
• Betof AS, Rabbani ZN, Hardee ME, et al Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification. Br J Cancer 2012;106:916–22
   PubMed Web of Science ®Google Scholar
• Aomatsu N, Yashiro M, Kashiwagi S, et al Carbonic anhydrase 9 is associated with chemosensitivity and prognosis in breast cancer patients treated with taxane and anthracycline. BMC Cancer 2014;14:400
   PubMed Web of Science ®Google Scholar
• Zheng G, Peng C, Jia X, et al ZEB1 transcriptionally regulated carbonic anhydrase 9 mediates the chemoresistance of tongue cancer via maintaining intracellular pH. Mol Cancer 2015;14:84
   PubMed Web of Science ®Google Scholar
• Türeci O, Sahin U, Vollmar E, et al Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Proc Natl Acad Sci USA 1998;95:7608–13
   PubMed Web of Science ®Google Scholar
• Loncaster JA, Harris AL, Davidson SE, et al Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 2001;61:6394–9
   PubMed Web of Science ®Google Scholar
• Hsieh M-J, Chen K-S, Chiou H-L, Hsieh Y-S. Carbonic anhydrase XII promotes invasion and migration ability of MDA-MB-231 breast cancer cells through the p38 MAPK signaling pathway. Eur J Cell Biol 2010;89:598–606
   PubMed Web of Science ®Google Scholar
• Chien M-H, Ying T-H, Hsieh Y-H, et al Tumor-associated carbonic anhydrase XII is linked to the growth of primary oral squamous cell carcinoma and its poor prognosis. Oral Oncol 2012;48:417–23
   PubMed Web of Science ®Google Scholar
• Watson PH, Chia SK, Wykoff CC, et al Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma. Br J Cancer 2003;88:1065–70
   PubMed Web of Science ®Google Scholar
• Tafreshi NK, Lloyd MC, Bui MM, et al Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases. Subcell Biochem 2014;75:221–54
   PubMedGoogle Scholar
• Neri D, Supuran CT. Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 2011;10:767–77
   PubMed Web of Science ®Google Scholar
• Grandane A, Tanc M, Di Cesare Mannelli L, et al 6-Substituted sulfocoumarins are selective carbonic anhdydrase IX and XII inhibitors with significant cytotoxicity against colorectal cancer cells. J Med Chem 2015;58:3975–83
   PubMed Web of Science ®Google Scholar
• Teixeira SA, Pezuk JA, Brassesco MS, et al Abstract C292: inhibition of carbonic anhydrase (9 and 12) decreases cell proliferation and gene expression in human glioblastoma cell. Mol Cancer Ther 2014;12:C292
   Web of Science ®Google Scholar
• Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci 2012;125:5591–6
   PubMed Web of Science ®Google Scholar
• Gajewski TF, Schreiber H, Fu Y-X. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013;14:1014–22
   PubMed Web of Science ®Google Scholar
• Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008;27:5904–12
   PubMed Web of Science ®Google Scholar
• Xing F, Saidou J, Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci (Landmark Ed) 2010;15:166–79
   PubMed Web of Science ®Google Scholar
• Kharaishvili G, Simkova D, Bouchalova K, et al The role of cancer-associated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance. Cancer Cell Int 2014;14:41
   PubMed Web of Science ®Google Scholar
• Gelmon KA, Eisenhauer EA, Harris AL, et al Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development? J Natl Cancer Inst 1999;91:1281–7
   PubMed Web of Science ®Google Scholar
• Macheda ML, Stacker SA. Importance of Wnt signaling in the tumor stroma microenvironment. Curr Cancer Drug Targets 2008;8:454–65
   PubMed Web of Science ®Google Scholar
• Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006;6:506–20
   PubMed Web of Science ®Google Scholar
• Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012;196:395–406
   PubMed Web of Science ®Google Scholar
• Huber V, De Milito A, Harguindey S, et al Proton dynamics in cancer. J Transl Med 2010;8:57
   PubMed Web of Science ®Google Scholar
• Xu K, Mao X, Mehta M, et al Elucidation of how cancer cells avoid acidosis through comparative transcriptomic data analysis. PLoS One 2013;8:e71177
   PubMed Web of Science ®Google Scholar
• Szakács G, Paterson JK, Ludwig JA, et al Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006;5:219–34
   PubMed Web of Science ®Google Scholar
• Persidis A. Cancer multidrug resistance. Nat Biotechnol 1999;17:94–5
   PubMed Web of Science ®Google Scholar
• Bao L, Haque A, Jackson K, et al Increased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model. Am J Pathol 2011;178:838–52
   PubMed Web of Science ®Google Scholar
• Wu H, Hait WN, Yang J-M. Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res 2003;63:1515–19
   PubMed Web of Science ®Google Scholar
• Donnenberg VS, Donnenberg AD. Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol 2005;45:872–7
   PubMed Web of Science ®Google Scholar
• Alfarouk KO, Stock C-M, Taylor S, et al Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int 2015;15:71
   PubMed Web of Science ®Google Scholar
• Siemann DW, ed. Tumor vasculature: a target for anticancer therapies. In: Vascular-targeted therapies in oncology. Chichester: John Wiley & Sons, Ltd; 2006:1–8
   Google Scholar
• Alfarouk KO, Ibrahim ME, Gatenby RA, Brown JS. Riparian ecosystems in human cancers. Evol Appl 2013;6:46–53
   PubMed Web of Science ®Google Scholar
• Lloyd MC, Alfarouk KO, Verduzco D, et al Vascular measurements correlate with estrogen receptor status. BMC Cancer 2014;14:279
   PubMed Web of Science ®Google Scholar
• Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther 2008;7:3670–84
   PubMed Web of Science ®Google Scholar
• Daniel C, Bell C, Burton C, et al The role of proton dynamics in the development and maintenance of multidrug resistance in cancer. Biochim Biophys Acta 2013;1832:606–17
   PubMed Web of Science ®Google Scholar
• Rauch C. On the relationship between drug’s size, cell membrane mechanical properties and high levels of multi drug resistance: a comparison to published data. Eur Biophys J 2009;38:537–46
   PubMed Web of Science ®Google Scholar
• Rauch C. Toward a mechanical control of drug delivery. On the relationship between Lipinski’s 2nd rule and cytosolic pH changes in doxorubicin resistance levels in cancer cells: a comparison to published data. Eur Biophys J 2009;38:829–46
   PubMed Web of Science ®Google Scholar
• Raghunand N, Gillies RJ. pH and drug resistance in tumors. Drug Resist Updat 2000;3:39–47
   PubMed Web of Science ®Google Scholar
• Raghunand N, Martínez-Zaguilán R, Wright SH, Gillies RJ. pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs. Biochem Pharmacol 1999;57:1047–58
   PubMed Web of Science ®Google Scholar
• Song CW, Griffin R, Park HJ. Influence of tumor pH on therapeutic response. In: Teicher B, ed. Cancer drug discovery and development: cancer drug Resistance. Totowa (NJ): Humana Press Inc.; 2006:21–43
   Google Scholar
• Noël J, Pouysségur J. Hormonal regulation, pharmacology, and membrane sorting of vertebrate Na+/H + exchanger isoforms. Am J Physiol 1995;268:C283–96
   PubMedGoogle Scholar
• Bookstein C, Xie Y, Rabenau K, et al Tissue distribution of Na+/H + exchanger isoforms NHE2 and NHE4 in rat intestine and kidney. Am J Physiol 1997;273:C1496–505
   PubMedGoogle Scholar
• Biemesderfer D, Pizzonia J, Abu-Alfa A, et al NHE3: a Na+/H + exchanger isoform of renal brush border. Am J Physiol 1993;265:F736–42
   PubMedGoogle Scholar
• Orlowski J, Kandasamy RA, Shull GE. Molecular cloning of putative members of the Na/H exchanger gene family. cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins. J Biol Chem 1992;267:9331–9
   PubMed Web of Science ®Google Scholar
• Bookstein C, Musch MW, DePaoli A, et al A unique sodium-hydrogen exchange isoform (NHE-4) of the inner medulla of the rat kidney is induced by hyperosmolarity. J Biol Chem 1994;269:29704–9
   PubMed Web of Science ®Google Scholar
• Xinhan L, Matsushita M, Numaza M, et al Na+/H + exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin. Am J Physiol Cell Physiol 2011;301:C1431–44
   PubMed Web of Science ®Google Scholar
• Schwede M, Garbett K, Mirnics K, et al Genes for endosomal NHE6 and NHE9 are misregulated in autism brains. Mol Psychiatry 2013;19:277–9
   PubMed Web of Science ®Google Scholar
• Onishi I, Lin PJC, Numata Y, et al Organellar (Na+, K+)/H + exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells. Oncol Rep 2012;27:311–17
   PubMed Web of Science ®Google Scholar
• Johnson LR, Ghishan FK, Kaunitz JD, et al Physiology of the gastrointestinal tract. Chapter 66. Amsterdam: Elsevier; 2012:1799. ISBN: 978-0-12-382026-6
   Google Scholar
• Gawenis LR, Greeb JM, Prasad V, et al Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H + exchanger. J Biol Chem 2005;280:12781–9
   PubMed Web of Science ®Google Scholar
• Nakamura N, Tanaka S, Teko Y, et al Four Na+/H + exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J Biol Chem 2005;280:1561–72
   PubMed Web of Science ®Google Scholar
• Helbig G, Christopherson KW. Bhat-Nakshatri., et al NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 2003;278:21631–8
   PubMed Web of Science ®Google Scholar
• Zhao M, Gao Y, Wang L, et al Overexpression of integrin-linked kinase promotes lung cancer cell migration and invasion via NF-κB-mediated upregulation of matrix metalloproteinase-9. Int J Med Sci 2013;10:995–1002
   PubMed Web of Science ®Google Scholar
• Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 2009;1:a000141
   PubMed Web of Science ®Google Scholar
• Samuvel DJ, Sundararaj KP, Nareika A, et al Lactate boosts TLR4 signaling and NF-kappaB pathway-mediated gene transcription in macrophages via monocarboxylate transporters and MD-2 up-regulation. J Immunol 2009;182:2476–84
   PubMed Web of Science ®Google Scholar
• Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006;441:431–6
   PubMed Web of Science ®Google Scholar
• Liu F, Bardhan K, Yang D, et al NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression. J Biol Chem 2012;287:25530–40
   PubMed Web of Science ®Google Scholar
• Parfentjev IA, Suntzeff VD, Devrient WK. The influence of various preparations of lactic acid and sugars on the growth of transplanted tumors: II. Mouse Sarcoma 180. Am J Cancer 1934;20:117–36
   Google Scholar
• Lee Y-J, Kang I-J, Bünger R, et al Mechanisms of pyruvate inhibition of oxidant-induced apoptosis in human endothelial cells. Microvasc Res 2003;66:91–101
   PubMed Web of Science ®Google Scholar