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The Ph paradigm in cancer


Malignant tissues show a peculiar feature regarding pH: while normal tissues have a higher extracellular pH than intracellular pH, in cancer is exactly the opposite. This phenomenon is called the inversion of the pH gradient and is now considered a hallmark of malignancy. For some time, this inverted pH gradient was believed to be a secondary effect of cancer. Now, it is becoming clear that pH inversion is not an innocent consequence, but a key player in the etiopathogenesis of cancer. Therefore, addressing this issue as part of an integral treatment of neoplasia should be a necessary step for improving cancer patients’ outcomes. However, the knowledge acquired in this regard through basic research has not reached bedside treatments. The most striking fact is that there are repurposed drugs and nutraceuticals with low or no toxicity that can modify the pH gradient inversion. However, these drugs have not even been tested in cancer treatment.

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Fig. 1: pH gradient inversion starts with the neoplastic transformation with the increased activity of NHE1 that increases intracellular alkalosis through the exportation of protons (H+).


  1. 1.

    Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M, 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  CAS  Google Scholar 

  2. 2.

    Gottlieb RA, Nordberg J, Skowronski E, Babior BM. Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification. Proc Natl Acad Sci. 1996;93:654–8.

    PubMed  CAS  Google Scholar 

  3. 3.

    Horvat B, Taheri S, Salihagić A. Tumour cell proliferation is abolished by inhibitors of Na+ H+ and HCO3− Cl− exchange. Eur J Cancer. 1993;29:132–7.

    Google Scholar 

  4. 4.

    Lucas CA, Gillies RJ, Olson JE, Giuliano KA, Martinez R, Sneider JM. Intracellular acidification inhibits the proliferative response in BALB/c‐3T3 cells. J Cell Physiol. 1988l;136:161–7.

    PubMed  CAS  Google Scholar 

  5. 5.

    Shrode LD, Tapper H, Grinstein S. Role of intracellular pH in proliferation, transformation, and apoptosis. J Bioenerg Biomembranes. 1997;29:393–9.

    CAS  Google Scholar 

  6. 6.

    Warburg O, Posener K, Negelein E. Uber den Stoffwechsel der Carcinomzelle. Biochem. Z. 1924;152:309–44.

  7. 7.

    Newell K, Franchi A, Pouyssegur J, Tannock I. Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci. 1993;90:1127–31.

    PubMed  CAS  Google Scholar 

  8. 8.

    Yamagata M, Hasuda K, Stamato T, Tannock IF. The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase. Br J Cancer. 1998;77:1726.

    PubMed  PubMed Central  CAS  Google Scholar 

  9. 9.

    Schwartz L, Supuran C, Alfarouk OK. The Warburg effect and the hallmarks of cancer. Anti-Cancer Agents Medicinal Chem (Former Curr Medicinal Chem-Anti-Cancer Agents). 2017;17:164–70.

    CAS  Google Scholar 

  10. 10.

    McIntyre A, Harris AL. The role of ph regulation in cancer progression. In: Cramer TA, Schmitt C, editors. Metabolism in cancer. Recent results in cancer research, Vol 207. Cham: Springer; 2016. p. 93–134.

  11. 11.

    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.

    PubMed  CAS  Google Scholar 

  12. 12.

    Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 1999;59:5830–5.

    PubMed  CAS  Google Scholar 

  13. 13.

    Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci Stke 2007;2007:cm8.

    PubMed  Google Scholar 

  14. 14.

    Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 2010;330:1340–4.

    PubMed  CAS  Google Scholar 

  15. 15.

    Obre E, Rossignol R. Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Int J Biochem Cell Biol. 2015;59:167–81.

    PubMed  CAS  Google Scholar 

  16. 16.

    Chambard JC, Pouyssegur J. Intracellular pH controls growth factor-induced ribosomal protein S6 phosphorylation and protein synthesis in the G0→G1 transition of fibroblasts. Exp cell Res. 1986;164:282–94.

    PubMed  CAS  Google Scholar 

  17. 17.

    Winkler MM, Matson GB, Hershey JW, Bradbury EM. 31P-NMR study of the activation of the sea urchin egg. Exp cell Res. 1982;139:217–22.

    PubMed  CAS  Google Scholar 

  18. 18.

    Peppicelli S, Bianchini F, Calorini L. Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev. 2014;33:823–32.

    PubMed  CAS  Google Scholar 

  19. 19.

    Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 2013;73:1524–35.

    PubMed  PubMed Central  CAS  Google Scholar 

  20. 20.

    Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, et al. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res 2009;69:2260–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Webb SD, Sherratt JA, Fish RG. Alterations in proteolytic activity at low pH and its association with invasion: a theoretical model. Clin Exp Metastasis. 1999;17:397–407.

    PubMed  CAS  Google Scholar 

  22. 22.

    Lardner A. The effects of extracellular pH on immune function. J Leukoc Biol. 2001;69:522–30.

    PubMed  CAS  Google Scholar 

  23. 23.

    Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res 2016;76:1381–90.

    PubMed  CAS  Google Scholar 

  24. 24.

    Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology 2013;2:e22058.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72:2746–56.

    PubMed  CAS  Google Scholar 

  26. 26.

    Gerweck LE, Vijayappa S, Kozin S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Therapeutics. 2006;5:1275–9.

    CAS  Google Scholar 

  27. 27.

    De Milito A, Fais S. Tumor acidity, chemoresistance and proton pump inhibitors. Future Med. 2005;1:779–86.

  28. 28.

    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  CAS  Google Scholar 

  29. 29.

    Thews O, Gassner B, Kelleher DK, Schwerd G, Gekle M. Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 2006;8:143–52.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Stock C, Schwab A. Protons make tumor cells move like clockwork. Pflügers Arch-Eur J Physiol. 2009;458:981–92.

    CAS  Google Scholar 

  31. 31.

    Huber V, De Milito A, Harguindey S, Reshkin SJ, Wahl ML, Rauch C, et al. Proton dynamics in cancer. J Transl Med. 2010;8:57.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol. 2012;23:352–61.

    PubMed  CAS  Google Scholar 

  33. 33.

    DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2:e1600200.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kroemer G. Mitochondria in cancer. Nature Publishing Group; 2006.

  35. 35.

    Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, et al. Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol. 2017; 43:74–89.

  36. 36.

    Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology. 2013;2:e22058.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Bohloli M, Atashi A, Soleimani M, Kaviani S, Anbarlou A. Investigating effects of acidic pH on proliferation, invasion and drug-induced apoptosis in lymphoblastic leukemia. Cancer Microenviron 2016;9:119–26.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 2000;61:6020–4.

    Google Scholar 

  39. 39.

    Cosse JP, Michiels C. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anti-Cancer Agents Medicinal Chem (Former Curr Medicinal Chem-Anti-Cancer Agents). 2008;8:790–7.

    CAS  Google Scholar 

  40. 40.

    Resendis-Antonio O, Checa A, Encarnación S. Modeling core metabolism in cancer cells: surveying the topology underlying the Warburg effect. PloS ONE. 2010;5:e12383.

  41. 41.

    Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703–7.

    PubMed  CAS  Google Scholar 

  42. 42.

    Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Brand KA, Hermfisse U. Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 1997;11:388–95.

    PubMed  CAS  Google Scholar 

  44. 44.

    Brand K. Aerobic glycolysis by proliferating cells: protection against oxidative stress at the expense of energy yield. J Bioenerg Biomembranes. 1997;29:355–64.

    CAS  Google Scholar 

  45. 45.

    Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41:211–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  46. 46.

    Koltai T. Triple-edged therapy targeting intracellular alkalosis and extracellular acidosis in cancer. Semin Cancer Biol. 2017;43:139–46.

    PubMed  CAS  Google Scholar 

  47. 47.

    Koltai T, Reshkin SJ, Harguindey S. An innovative approach to understanding and treating cancer: targeting ph: from etiopathogenesis to new therapeutic avenues. Academic Press; 2020.

  48. 48.

    Harguindey S, Koltai T, Reshkin SJ. Curing cancer? further along the new pH-centric road and paradigm. Oncoscience. 2018;5:132.

    PubMed  PubMed Central  CAS  Google Scholar 

  49. 49.

    Harguindey S, Arranz JL, Wahl ML, Orive G, Reshkin SJ. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res. 2009;29:2127–36.

    PubMed  CAS  Google Scholar 

  50. 50.

    Matthews H, Ranson M, Kelso MJ. Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: an orally active anti‐cancer drug waiting for its call‐of‐duty? Int J Cancer. 2011;129:2051–61.

    PubMed  CAS  Google Scholar 

  51. 51.

    Reshkin JS, Cardone RA, Harguindey S. Na+-H+ exchanger, pH regulation and cancer. Recent Pat Anti-cancer Drug Discov. 2013;8:85–99.

    CAS  Google Scholar 

  52. 52.

    Slepkov E, Fliegel L. Structure and function of the NHE1 isoform of the Na+/H+ exchanger. Biochem Cell Biol. 2002;80:499–508.

    PubMed  CAS  Google Scholar 

  53. 53.

    Dana P, Vaeteewoottacharn K, Kariya R, Matsuda K, Wongkham S, Okada S. Repurposing cimetidine for cholangiocarcinoma: antitumor effects in vitro and in vivo. Oncol Lett. 2017;13:1432–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  54. 54.

    Harguindey S, Arranz JL, Orozco JD, Rauch C, Fais S, Cardone RA, 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  PubMed Central  Google Scholar 

  55. 55.

    Teicher BA, Liu SD, Liu JT, Holden SA, Herman TS. A carbonic anhydrase inhibitor as a potential modulator of cancer therapies. Anticancer Res 1993;13(5A):1549–56.

    PubMed  CAS  Google Scholar 

  56. 56.

    Ahlskog JK, Dumelin CE, Trüssel S, Mårlind J, Neri D. In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives. Bioorg Med Chem Lett. 2009;19:4851–6.

    PubMed  CAS  Google Scholar 

  57. 57.

    Amorim R, Pinheiro C, Miranda-Gonçalves V, Pereira H, Moyer MP, Preto A, et al. Monocarboxylate transport inhibition potentiates the cytotoxic effect of 5-fluorouracil in colorectal cancer cells. Cancer Lett 2015;365:68–78.

    PubMed  CAS  Google Scholar 

  58. 58.

    Fang J, Zhang S, Xue X, Zhu X, Song S, Wang B, et al. Quercetin and doxorubicin co-delivery using mesoporous silica nanoparticles enhance the efficacy of gastric carcinoma chemotherapy. Int J Nanomed. 2018;13:5113.

    CAS  Google Scholar 

  59. 59.

    Bakar NS, Kamali F, Brown CD. Effect of statins on functional expression of membrane transporters in L6 rat skeletal muscle cells. J Biomed Clin Sci (JBCS). 2017;1:17–26.

    Google Scholar 

  60. 60.

    Mehibel M, Ortiz-Martinez F, Voelxen N, Boyers A, Chadwick A, Telfer BA, et al. Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters. Sci Rep. 2018;8:16804.

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Monzani E, Shtil AA, La Porta CA. The water channels, new druggable targets to combat cancer cell survival, invasiveness and metastasis. Curr Drug Targets. 2007;8:1132–7.

    PubMed  CAS  Google Scholar 

  62. 62.

    Bing MA, Yang X, Li T, Yu HM, Li XJ. Inhibitory effect of topiramate on Lewis lung carcinoma metastasis and its relation with AQP1 water channel. Acta Pharm Sin. 2004;25:54–60.

    Google Scholar 

  63. 63.

    Marathe K, McVicar N, Li A, Bellyou M, Meakin S, Bartha R. Topiramate induces acute intracellular acidification in glioblastoma. J Neuro-Oncol. 2016;130:465–72.

    CAS  Google Scholar 

  64. 64.

    Walsh M, Fais S, Spugnini EP, Harguindey S, Izneid TA, Scacco L, et al. Proton pump inhibitors for the treatment of cancer in companion animals. J Exp Clin Cancer Res. 2015;34:93.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Spugnini E, Fais S. Proton pump inhibition and cancer therapeutics: a specific tumor targeting or it is a phenomenon secondary to a systemic buffering?. Semin. Cancer Biol. 2017;43: 111–8.

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Third International Acid-Base Symposium, June 24–28, 2018, Smolenice Castle, Slovakia.

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This article is published as part of a supplement sponsored by NuOmix-Research k.s. The conference was financially supported by Protina Pharmazeutische GmbH, Germany and Sirius Pharma, Germany, and organized by NuOmix-Research k.s. Neither company had any role in writing of the manuscript.

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Correspondence to Tomas Koltai.

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Koltai, T. The Ph paradigm in cancer. Eur J Clin Nutr 74, 14–19 (2020).

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