Past, present and future of cancer and neurodegenerative diseases research and treatment with emphasis on breast and brain cancer
Main Article Content
Abstract
“When the solution of a scientific problem is neither possible at the present time nor can be foreseen in the future this may mean that the answer that we are so desperately looking for can be waiting for us hiding in the past”. L. Arranz
In its diverse forms in nature (H+, H1, H2, H3O+), it is becoming increasingly evident that hydrogen plays a fundamental role in many areas of both human life and the entire planetary ecosystem. It has been postulated that hydrogen was the first molecule detected just after the Big Bang, a simple product that can be easily transformed into different energy compounds. There are many aspects of pH-mediated damage, from acid rain and the acidification of the seas to cellular apoptosis. On the contrary, the good news is that modern hydrogen technologies hold the promise of obtaining limitless amounts of clean energy. Also, the hydrogen obtained by the decomposition of water through renewable energies, like solar or wind, is transformed into energy as a clean fuel. Since this methodology uses the most abundant raw material, water, it can accumulate great quantities of energy with a very low environmental impact.
In the world of medicine, the dynamics of the hydrogen ion (protons or H+) is a more realistic manner of expressing changes in pH and/or acid-base homeostasis and pathophysiology. Recently, the pH-centered anticancer perspective has been extended to include the etiology, pathogenesis, and treatment of neurodegenerative diseases (HNDDs), all under the same integral and unitary H+-perspective.
From the classical genetic perspective, the nature of cancer is thought to include a multiplicity of diseases that require a large variety and combination of generally toxic drugs created to kill every neoplasm. However, from a phenotypic standpoint, cancer is a highly organized and uniform disease having selective hallmarks in all malignant tumors irrespective of their genetic and tissue differences. This is logical since all solid tumors, and even leukemias, share most molecular, metabolic, biochemical, and pathophysiological characteristics that are independent of their genetic makeup.
It is well known that there is a general mechanism that supports any single transformation, growth, progression, invasion, and metastasis of any malignant tumor. Such an integral and hierarchically organized progressive and destructive process is also in full accord with what Otto Warburg once said: "The causes of cancer are countless, but they all work through the same mechanism". Recently, the new paradigm on cancer has been associated to the etiopathogenesis of HNDDs in a comprehensive article in this same journal. No matter that from the point of view of metabolism, a massive number of intermediary causes of cancer have been discovered and well-identified, it can be demonstrated that they act through a final and integral mechanism represented by an increase in cellular pH mainly mediated by the upregulation of the Na+/H+ (NHE1) (Table 1).
Article Details
How to Cite
HARGUINDEY, Salvador et al.
Past, present and future of cancer and neurodegenerative diseases research and treatment with emphasis on breast and brain cancer.
Medical Research Archives, [S.l.], v. 14, n. 7, july 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7576>. Date accessed: 06 aug. 2026.
doi: https://doi.org/10.18103/mra.v14i7.7576.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Ares JR, Leardini F, Sanchez C, Fernandez J. El hidrógeno verde como vector energético del futuro | TÜV Rheinland. Encuentros Multidiscip. 2019;62:1–10.
2. Chen C, Wang X, Yang T, et al.The pH perspective of cancer: From Warburg's misconception to therapeutic targeting of pH regulating proteins. Crit Rev Oncol Hematol. 2026;217:105051. doi:10.1016/j.critrevon c.2025.105051.
3. Harguindey S. Use of Na+/H+ antiporter inhibitors as a novel approach to cancer treatment. In: Simchowitz EJ, ed. Amiloride and Its Analogs: Unique Cation Transport Inhibitors. New York; 1992:317–334.
4. Harguindey S, Reshkin SJ. The new pH-centric anticancer paradigm in Oncology and Medicine; SCB, 2017. Semin Cancer Biol. 2017;43:1–4.
5. Celi, A.B., Mechali, A., Beltramone, N. et al. Targeting pH regulation in cancer: combined mild alkaline treatment and NHE1 inhibition as a potential therapy for clear cell renal cell carcinoma. Mol Cell Biochem 481, 1875–1887 (2026). https://doi.org/10.1007/s11010-026-05511-3).
6. Schwartz L, Buhler L, Icard P, et al. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014;34:973–980.
7. Harguindey S, Orive G, Cacabelos R, et al. An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs) and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS). Neuropsychiatr Dis Treat. 2008;4:1073–1084.
8. Harguindey S, Alfarouk K, Orozco JP, et al. Hydrogen Ion Dynamics as the Fundamental Link between Neurodegenerative Diseases and Cancer: Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis on Multiple Sclerosis. Int J Mol Sci. 2022;23 (5). https://doi.org/10.3390/ijms23052454
9. Fang B, Wang D, Huang M, Yu G, Li H. Hypothesis on the relationship between the change in intracellular pH and incidence of sporadic Alzheimer's disease or vascular dementia. Int J Neurosci. 2010;120:591–595.
10. Schwartz L, Peres S, Jolicoeur M, da Veiga Moreira J. Cancer and Alzheimer's disease: intracellular pH scales the metabolic disorders. Biogerontology. 2020;21:683–694.
11. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
12. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
13. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12:31–46.
14. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314.
15. Harguindey S, Reshkin SJ, Alfarouk KO. The Prime and Integral Cause of Cancer in the Post-Warburg Era. Cancers (Basel). 2023;15.
16. Harguindey S, Reshkin SJ, Devesa J, et al. The Oncoming Hydrogen Era and The New Paradigm of Cancer and Neurodegenerative Diseases Based on the Hydrogen Ion Dynamics on Cellular Homeostasis and Metabolism - from Etiopathogenesis to Treatment. Medical Research Archives 2026, 14, 3, 1-4. doi: https://doi.org/10.18103/mra.v14i1.7161
17. Harguindey SS, Kolbeck RC, Bransome ED. Letter: Ureterosigmoidostomy and cancer: new observations. Ann Intern Med. 1975;83:833.
18. Harguindey S. Hydrogen ion dynamics and cancer: An appraisal. Med Pediatr Oncol. 1982;10:217–236.
19. Orive G, Reshkin SJ, Harguindey S, Pedraz JL. Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis. Br J Cancer. 2003;89:1395–1399.
20. Huber V, De Milito A, Harguindey S, et al. Proton dynamics in cancer. J Transl Med. 2010;8:57.
21. Harguindey S, Orozco JP, Alfarouk KO, Devesa J. Hydrogen ion dynamics of cancer and a new molecular, biochemical and metabolic approach to the etiopathogenesis and treatment of brain malignancies. Int J Mol Sci. 2019;20. doi:10.3390/ijms20174278.
22. Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ. 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.
23. Harguindey S, Stanciu D, Devesa J, et al. Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases. Semin Cancer Biol. 2017;43: 157–179.
24. Nagata H, Che XF, Miyazawa K, et al. Rapid decrease of intracellular pH associated with inhibition of Na+/H+ exchanger precedes apoptotic events in the MNK45 and MNK74 gastric cancer cell lines treated with 2-aminophenoxazine-3-one. Oncol Rep. 2011;25:341–346.
25. Quach CHT, Kim HD, Coomber BL, et al. Mild Alkalization Acutely Triggers the Warburg Effect by Enhancing Hexokinase Activity via Voltage-Dependent Anion Channel Binding. PLoS One. 2016;11:e0159529.
26. Alfarouk KO, Muddathir AK, Shayoub MEA, 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.
27. 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;14:2185–2197.
28. Grillo-Hill BK, Choi C, Jimenez-Vidal M, Barber DL. Increased H+ efflux is sufficient to induce dysplasia and necessary for viability with oncogene expression. Elife. 2015;4.
29. Amith SR, Wilkinson JM, Fliegel L. Assessing Na+/H+ exchange and cell effector functionality in metastatic breast cancer. Biochim Open. 2016;2:16–23.
30. Liu Y, White KA, Barber DL, et al. Intracellular pH dynamics regulates intestinal stem cell lineage specification. Nat Commun. 2023;14:1–18.
31. Perona R, Portillo F, Giraldez F, Serrano R. Transformation and pH homeostasis of fibroblasts expressing yeast H(+)-ATPase containing site-directed mutations. Mol Cell Biol. 1990;10:4110.
32. Harguindey S, Alfarouk K, Polo Orozco J, et al. A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer Based upon Its Hydrogen Ion Dynamics. Int J Mol Sci. 2020;21:1110.
33. Harguindey S, Arranz JL, Wahl ML, Orive G, Reshkin SJ. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res. 2009;29:2127–2136.
34. Schwartz L, Seyfried T, Alfarouk KO, et al. Out of Warburg effect: An effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin Cancer Biol. 2017;43:134–138.
35. Greco MR, Fracasso F, Cannone S, et al. Acidosis Drives Vasculogenic Mimicry in PDAC CSCs via Na+/H+ Exchanger Isoform 1 (NHE1) and Calcium Entry. Cells. 2026; 15(10):865. https://doi.org/10.3390/cells15100865
36. Koltai T, Reshkin SJ, Baltazar F, Fliegel L. Prostate Cancer Metabolism. In: Prostate Cancer Metabolism: From Biochemistry to Therapeutics. Elsevier; 2021. doi:10.1016/C2020-0-03559-0.
37. Harguindey S, Henderson ES, Naeher C. Effects of systemic acidification of mice with Sarcoma 180. Cancer Res. 1979;39:4364–4371.
38. Hippocrates. On Airs, Waters, and Places. The Internet Classics Archive.
http://classics.mit.edu/Hippocrates/airwatpl.html.
39. Parks SK, Chiche J, Pouysségur J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer. 2013;13:611–623.
40. Kroemer G, Pouyssegur J. Tumor Cell Metabolism: Cancer's Achilles' Heel. Cancer Cell. 2008;13:472–482. doi:10.1016/j.ccr.2008.05.005.
41. Alfarouk KO, Muddathir AK, Shayoub MEA. Tumor acidity as evolutionary spite. Cancers (Basel). 2011;3: 408–414.
42. Huber V, Camisaschi C, Berzi A, et al. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol. 2017;43:74–89.
43. Cannon WB. Organization for Physiological Homeostasis. Physiol Rev. 1929;9:399–431.
44. Selye H. The evolution of the stress concept. Am Sci. 1973;61:692–699.
45. Harguindey S, Katin M, Edgerton F, Takita H. Hierarchical organization, integrations in biology and cancer, balance loss, and a question on modernism. Med Hypotheses. 1981;7:1123–1132.
46. Rauch C, Braet F, Thome L, et al. Cell Membranes, Cytosolic pH and Drug Transport in Cancer and MDR: Physics, Biochemistry and Molecular Biology. Mult Drug Resist. 2009;0044:1–24.
47. Cone C. D. Unified theory on the basic mechanism of normal mitotic control and oncogenesis J Theor biol 1971,30,151-181.
48. An J, Zhang L, Duan Y, Pu S, Peng F. Sodium's role and therapeutic targeting in cancer. Trends Pharmacol Sci. 2026 Jan;47(1):53-65. doi: 10.1016/j.tips.2025.10.015. Epub 2025 Nov 28. PMID: 41318248.)
49. Lim H, Albatany M, Martínez-Santiesteban F, Bartha R, Scholl TJ. Longitudinal Measurements of Intra- and Extracellular pH Gradient in a Rat Model of Glioma. Tomography. 2018;4:46.
50. Honasoge A, Sontheimer H. Involvement of tumor acidification in brain cancer pathophysiology. Front Physiol. 2013;4.
51. di Cristofori A, Carrabba G, Faou P, et al. The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma. Oncotarget. 2015;6:17514–17531.
52. Spugnini EP, Sonveaux P, Stock C, et al. Proton channels and exchangers in cancer. Biochim Biophys Acta - Biomembr. 2014;1848:2715–2726.
53. Perek N, Denoyer D, Dubois F, Koumanov F. Malignant gliomas display altered plasma membrane potential and pH regulation--interaction with Tc-99m-MIBI and Tc-99m-Tetrofosmin uptakes. Gen Physiol Biophys. 2002;21:381–404.
54. Luciani F, Spada M, De Milito A, et al. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst. 2004;96:1702–1713.
55. Mboge MY, Mahon BP, McKenna R, Frost SC. Carbonic Anhydrases: Role in pH Control and Cancer. Metabolites. 2018;8:19.
56. Shirmanova MV, Druzhkova IN, Lukina MM, et al. Chemotherapy with cisplatin: insights into intracellular pH and metabolic landscape of cancer cells in vitro and in vivo. Sci Rep. 2017;7:8911.
57. Miranda-Goncalves V, Reis RM, Baltazar F. Lactate Transporters and pH Regulation: Potential Therapeutic Targets in Glioblastomas. Curr Cancer Drug Targets. 2016;16:388–399.
58. Raudenska M, Balvan J, Fojtu M, Gumulec J, Masarik M. Unexpected therapeutic effects of cisplatin. Metallomics. 2019;11:1182–1199.
59. Tamtaji OR, Mirzaei H, Reiter RJ, et al. New trends in glioma cancer therapy: Targeting Na+ /H + exchangers. J Cell Physiol. 2020;235:658–665.
60. Guan X, Luo L, Sun W, et al. Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas. J Exp Clin Cancer Res. 2018;37.
61. Omran Z, Scaife P, Stewart S, Rauch C. Physical and biological characteristics of multi drug resistance (MDR): An integral approach considering pH and drug resistance in cancer. Semin Cancer Biol. 2017;43:42–48.
62. Zhu W, Carney KE, Pigott VM, et al. Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1. Carcinogenesis. 2016;37:839–851.
63. Reshkin SJ, Cardone RA, Harguindey S. Na+-H+ exchanger, pH regulation and cancer. Recent Pat Anticancer Drug Discov. 2013;8:85–99.
64. Cardone RA, Casavola V, Reshkin SJ. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer. 2005;5:786–795.
65. Bellone M, Calcinotto A, Filipazzi P, et al. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology. 2013;2.
66. Lacroix R, Rozeman EA, Kreutz M, Renner K, Blank CU. Targeting tumor-associated acidity in cancer immunotherapy. Cancer Immunol Immunother. 2018;67:1331–1348.
67. Thews O, Riemann A. Tumor pH and metastasis: a malignant process beyond hypoxia. Cancer Metastasis Rev. 2019;38:113–129.
68. Harguindey S, Koltai T, Reshkin SJ. Curing cancer? Further along the new pH-centric road and paradigm. Oncoscience. 2018;5:132.
69. Albatany M, Li A, Meakin S, Bartha R. In vivo detection of acute intracellular acidification in glioblastoma multiforme following a single dose of cariporide. Int J Clin Oncol. 2018;23:812–819.
70. Aggarwal M, Kondeti B, McKenna R. Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review. Expert Opin Ther Pat. 2013;23:717–724.
71. Pillai SR, Damaghi M, Marunaka Y, et al. Causes, consequences, and therapy of tumors acidosis. Cancer Metastasis Rev. 2019;38:205–222.
72. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, et al. Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy. Cancer Res. 2016;76:1381–1390.
73. Calcinotto A, Filipazzi P, Grioni M, et al. Modulation of Microenvironment Acidity Reverses Anergy in Human and Murine Tumor-Infiltrating T Lymphocytes. Cancer Res. 2012;72:2746–2756.
74. Martin NK, Robey IF, Gaffney EA, et al. Mathematical Biosciences A mathematical model of tumour and blood pHe regulation: The HCO À buffering system. Math Biosci. 2011;230:1–11.
75. Dighe A, Kulkarni S, Srivastava A, et al. Experimental and phylogenetic evidence for correlated gene expression evolution in endometrial and skin fibroblasts. iScience. 2024;27:108593.
76. Meads MB, Gatenby RA, Dalton WS. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer. 2009;9:665–674.
77. Robey IF, Baggett BK, Kirkpatrick ND, et al. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res. 2009;69:2260–2268.
78. Gatenby RA, Gillies RJ. A microenvironmental model of carcinogenesis. Nat Rev Cancer. 2008;8:56–61.
79. Moellering RE, Black KC, Krishnamurty C, et al. Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis. 2008;25:411–425.
80. Gatenby RA, Smallbone K, Maini PK, et al. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer. 2007;97:646–653.
81. Rich IN, Worthington-White D, Garden OA, Musk P. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood. 2000;95:1427–1434.
82. Nijhout HF. Metaphors and the role of genes in development. Bioessays. 1990;12:441–446.
83. Colen CB, Shen YM, Ghoddoussi F, et al. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia. 2011;13:620–632.
84. Geeviman K, Babu D, Prakash Babu P. Pantoprazole Induces Mitochondrial Apoptosis and Attenuates NF-κB Signaling in Glioma Cells. Cell Mol Neurobiol. 2018;38:1491–1504.
85. 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.
86. Harley W, Floyd C, Bhatt T, et al. Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas. Brain Res. 2010. doi:10.1016/j.brainres.2010.09.059.
87. Marathe K, McVicar N, Li A, et al. Topiramate induces acute intracellular acidification in glioblastoma. J Neurooncol. 2016;130:465–472.
88. Albatany M, Meakin S, Bartha R. The Monocarboxylate transporter inhibitor Quercetin induces intracellular acidification in a mouse model of Glioblastoma Multiforme: in-vivo detection using magnetic resonance imaging. Invest New Drugs. 2019;37:595–601.
89. Albatany M, Ostapchenko VG, Meakin S, Bartha R. Brain tumor acidification using drugs simultaneously targeting multiple pH regulatory mechanisms. J Neurooncol. 2019;144: 453–462.
90. Pérez-Escuredo J, Van Hée VF, Sboarina M, et al. Monocarboxylate transporters in the brain and in cancer. Biochim Biophys Acta. 2016;1863:2481–2497.
91. Miranda-Gonçalves V, Honavar M, Pinheiro C, et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro Oncol. 2013;15:172–188.
92. Anemone A, Consolino L, Arena F, Capozza M, Longo DL. Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH. Cancer Metastasis Rev. 2019;38:25–49.
93. Koltai T. Triple-edged therapy targeting intracellular alkalosis and extracellular acidosis in cancer. Semin Cancer Biol. 2017;43:139–146.
94. Chirasani SR, Leukel P, Gottfried E, et al. Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. Int J Cancer. 2013;132:843–853.
95. Binello E, Germano IM. Targeting glioma stem cells: a novel framework for brain tumors. Cancer Sci. 2011;102:1958–1966.
96. Gdovin MJ, Kadri N, Rios L, Holliday S, Jordan Z. Focal photodynamic intracellular acidification as a cancer therapeutic. Semin Cancer Biol. 2017;43:147–156.
97. Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm. 2015;93:52–79.
98. Kusuzaki K, Matsubara T, Murata H, et al. Natural extracellular nanovesicles and photodynamic molecules: is there a future for drug delivery? J Enzyme Inhib Med Chem. 2017;32:908–916.
99. Litan A, Langhans SA. Cancer as a channelopathy: ion channels and pumps in tumor development and progression. Front Cell Neurosci. 2015;9.
100. Besson P, Roger S, Neuhart S, et al. How do voltage-gated sodium channels enhance migration and invasiveness in cancer cells? Biochim Biophys Acta. 2015;1848:2493–2501.
101. Brackenbury WJ, Palmieri C. Blocking channels to metastasis: targeting sodium transport in breast cancer. Breast Cancer Res. 2023;25:1–3.
102. Purow B. Repurposing existing agents as adjunct therapies for glioblastoma. Neuro-Oncology Pract. 2016;3:154.
103. Harguindey S, Alfarouk K, Polo Orozco J, et al. Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era. Int J Mol Sci. 2020;21:7475.
104. Koltai T, Reshkin SJ, Harguindey S. An Innovative Approach to Understanding and Treating Cancer: Targeting PH From Etiopathogenesis to New Therapeutic Avenues. In: An Innovative Approach to Understanding and Treating Cancer: Targeting pH. Amsterdam: Elsevier; 2020. doi:10.1016/C2018-0-02687-0.
105. Egger SJ, Willson ML, Morgan J, et al. Platinum-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2017;6.
106. Cardone RA, Greco MR, Capulli M, et al. The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela. Int J Mol Sci. 2019;20:3694.
107. Alfarouk KO, Verduzco D, Rauch C, et al. The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer. Cancers (Basel). 2020;12:898.
108. Alfarouk KO, Stock CM, Taylor S, et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int. 2015;15:71.
109. Amith SR, Fliegel L. Na+/H+ exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics. Semin Cancer Biol. 2017;43:35–41.
110. Amith SR, Fliegel L. Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis. Cancer Res. 2013;73:1259–1264.
111. Lobo RC, Bhatt DL, Fan C, et al. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity. Front Cell Dev Biol. 2016;4.
112. Fliegel L. Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer. Rev Physiol Biochem Pharmacol. 2022;182:85–110.
113. Ma Z, Myers DP, Wu RF, et al. Function of ion transporters in maintaining acid-base homeostasis of the mammary gland and the pathophysiological role in breast cancer. Am J Physiol Regul Integr Comp Physiol. 2020;318:R98–R111.
114. Lee S, Axelsen TV, Andersen AP, et al. Na+,HCO3 − cotransport is functionally upregulated during human breast carcinogenesis and required for the inverted pH gradient across the plasma membrane. Pflügers Arch - Eur J Physiol. 2015;467:367–377.
115. Andersen AP, Sander LK, Kveiborg M, et al. The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms. Int J Cancer. 2018;142:2529–2542.
116. Boedtkjer E, Bunch L, Pedersen SF, et al. Contribution of Na+,HCO3(-)-cotransport to cellular pH control in human breast cancer: A role for the breast cancer susceptibility locus NBCn1 (SLC4A7). Int J Cancer. 2013; 132:1288–1299.
117. Pinheiro C, Longatto-Filho A, Ferreira L, et al. GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol. 2011;26:1279–1286.
118. Brisson L, Driffort V, Benoist L, et al. Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H(+) efflux in caveolae. Oncogene. 2011;30:2070–2076.
119. Fraser SP, Diss JK, Lloyd LJ, et al. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clin Cancer Res. 2005;11:5381–5389.
120. Cotter K, Capecci J, Martinez-Zaguilan R, et al. The a3 isoform of subunit a of the vacuolar ATPase localizes to the plasma membrane of invasive breast tumor cells and is overexpressed in human breast cancer. Oncotarget. 2016;7:46142–46157.
121. 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;1832:606–617.
122. von Schwarzenberg K, Lajber M, Vollmar AM, et al. V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. Mol Oncol. 2014;8:9–19.
123. Yu C, Chen X, Lin Y, et al. Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect. Oncotarget. 2017;8:83831–83844.
124. Amith SR, Fong S, Baksh S, Fliegel L. Na (+)/H (+)exchange in the tumor microenvironment: does NHE1 drive breast cancer carcinogenesis? Int J Dev Biol. 2015;59:367–377.
125. Zheng T, Jäättelä M, Liu B. pH gradient reversal fuels cancer progression. Int J Biochem Cell Biol. 2020; 125.
126. Mihaila RG. A minireview on NHE1 inhibitors. A rediscovered hope in oncohematology. Biomed Pap. 2015;159:519–526.
127. Flinck M, Kramer SH, Schnipper J, Andersen AP, Pedersen SF. The acid-base transport proteins NHE1 and NBCn1 regulate cell cycle progression in human breast cancer cells. Cell Cycle. 2018;17:1056–1067.
128. Lee S, Axelsen TV, Jessen N, et al. Disrupting Na+, HCO₃−-cotransporter NBCn1 (Slc4a7) delays murine breast cancer development. Oncogene. 2016;35:2112–2122.
129. Baenke F, Murillo-Garzon V, Norkin M, et al. Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival. J Pathol. 2015;237:152–165.
130. Goh W, Sleptsova-Freidrich I, Petrovic N. Use of proton pump inhibitors as adjunct treatment for triple-negative breast cancers. An introductory study. J Pharm Pharm Sci. 2014;17:439–446.
131. Morais-Santos F, Miranda-Gonçalves V, Pinto-Gomes S, et al. Targeting lactate transport suppresses in vivo breast tumour growth. Oncotarget. 2015;6:19177–19189.
132. Pinheiro C, Reis RM, Ricardo S, et al. Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology. 2010;56:860–867.
133. Boedtkjer E. Na+,HCO3- cotransporter NBCn1 accelerates breast carcinogenesis. Cancer Metastasis Rev. 2019;38:165–178.
134. Toft NJ, Axelsen TV, Pedersen HL, et al. Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival. Elife. 2021;10.
135. Yang M, Kozminski DJ, Wold LA, et al. Therapeutic potential for phenytoin: targeting Nav1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat. 2012;134: 603–615.
136. O'Grady S, Morgan MP, O'Grady S, Morgan MP. Calcium transport and signalling in breast cancer: Functional and prognostic significance. Semin Cancer Biol. 2021;72:19–26.
137. Kruger LC, Isom LL. Voltage-Gated Na+ Channels: Not Just for Conduction. Cold Spring Harb Perspect Biol. 2016;8:a029264.
138. Hernandez CM, Richards JR. Physiology, Sodium Channels. StatPearls. 2024.
139. Nelson M, Yang M, Millican-Slater R, Brackenbury WJ. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo. Oncotarget. 2015;6:32914–32929.
140. Dowd J, Hendin J, Fukushiro-Lopes DF, Laczynski D, Gentile S. Ion Channels in Breast Cancer: From Signaling to Therapy. In: Breast Cancer - From Biology to Medicine. InTech; 2017. doi:10.5772/66172.
141. Dhakan C, Anemone A, Ventura V, et al. Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging---Chemical Exchange Saturation Transfer Tumor pH Imaging. Metabolites. 2023;13:1161.
142. Ibrahim-Hashim A, Estrella V. Acidosis and Cancer: from Mechanism to Neutralization. Cancer Metastasis Rev. 2019;38:149.
143. Böhme I, Bosserhoff A. Extracellular acidosis triggers a senescence‐like phenotype in human melanoma cells. Pigment Cell Melanoma Res. 2020;33:41–51.
144. Germain D. Estrogen Carcinogenesis in Breast Cancer. Endocrinol Metab Clin North Am. 2011;40:473–484.
145. Meehan J, Ward C, Turnbull AK, et al. Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells. Oncotarget. 2017;8:42857–42875.
146. Kaloyianni M, Bourikas D, Koliakos G. The effect of insulin on Na+-H+ antiport activity of obese and normal subjects erythrocytes. Cell Physiol Biochem. 2001;11:253–258.
147. Moore RD, Gupta RK. Effect of insulin on intracellular ph as observed by 31p NMR spectroscopy. Int J Quantum Chem. 2009;18:83–92.
148. Williams B, Howard RL. Glucose-induced changes in Na+/H+ antiport activity and gene expression in cultured vascular smooth muscle cells. Role of protein kinase C. J Clin Invest. 1994;93:2623–2631.
149. Ramírez MA, Zavala AV, del Valle Lepez M, et al. Involvement of Intracellular pH in Vascular Insulin Resistance. Curr Vasc Pharmacol. 2019;17:440–446.
150. Lann D, LeRoith D. The role of endocrine insulin-like growth factor-I and insulin in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:371–379.
151. Gunter MJ, Hoover DR, Yu H, et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2009;101:48–60.
152. Clevenger CV, Furth PA, Hankinson SE, Schuler LA. The role of prolactin in mammary carcinoma. Endocr Rev. 2003;24:1–27.
153. Pedraz-Cuesta E, Christensen ST, Vendel Nielsen L, et al. Prolactin Signaling Stimulates Invasion via Na(+) /H(+) exchanger NHE1 in T47D Human Breast Cancer Cells. Mol Endocrinol. 2016. doi:10.1210/me.2015-1299.
154. Wennbo H, Gebre-Medhin M, Gritli-Linde A, et al. Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest. 1997;100:2744.
155. Koedoot E, Bost M, Sahai E, et al. Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes. Nat Commun. 2019;10:1–16.
156. Tavares-Valente D, Baltazar F, Moreira R, Queirós O. Cancer cell bioenergetics and pH regulation influence breast cancer cell resistance to paclitaxel and doxorubicin. J Bioenerg Biomembr. 2013;45:467–475.
157. Thews O, Gassner B, Kelleher DK, Schwerdt G, Gekle M. Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia. 2006;8:143–152.
158. Roepe PD, Wei LY, Cruz J, Carlson D. Lower electrical membrane potential and altered pHi homeostasis in multidrug-resistant (MDR) cells: further characterization of a series of MDR cell lines expressing different levels of P-glycoprotein. Biochemistry. 1993;32:11042–11056.
159. Taylor S, Spugnini EP, Assaraf YG, et al. Microenvironment acidity as a major determinant of tumor chemo-resistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resist Updat. 2015;23:69–78.
160. Barrière H, Bagdany M, Bhatt A, et al. CFTR modulates programmed cell death by decreasing intracellular pH in Chinese hamster lung fibroblasts. Am J Physiol Physiol. 2001;281:C810–C824.
161. Horvat B, Taheri S, Salihagić A. Tumour cell proliferation is abolished by inhibitors of Na+/H+ and HCO3-/Cl- exchange. Eur J Cancer. 1992;29A:132–137.
162. I.L. Cameron, I., L. Intervention of sodium flux as a target for cancer chemo- therapy. In: New Approaches to Cancer Chemotherapy, Academic Press, New York, 1984, pp. 355– 374.
163. Sparks RL, Pool TB, Smith NK, Cameron IL. Effects of amiloride on tumor growth and intracellular element content of tumor cells in vivo. Cancer Res. 1983;43:73–77.
164. Roger S, Besson P, Le Guennec JY. Involvement of a novel fast inward sodium current in the invasion capacity of a breast cancer cell line. Biochim Biophys Acta - Biomembr. 2003;1616:107–111.
165. He B, Zhang M, Zhu R. Na+/H+ exchanger blockade inhibits the expression of vascular endothelial growth factor in SGC7901 cells. Oncol Rep. 2010;23:79–87.
166. Kellen JA, Mirakian A, Kolin A. Antimetastatic effect of amiloride in an animal tumour model. Anticancer Res. 1988;8:1373–1376.
167. Evans DM, Sloan-Stakleff K, Arvan M, Guyton DP. Time and dose dependency of the suppression of pulmonary metastases of rat mammary cancer by amiloride. Clin Exp Metastasis. 1998;16:353–357.
168. Matthews H, Ranson M, Kelso MJ, et al. 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;129:2051–2061.
169. He B, Deng C, Zhang M, Zou D, Xu M. Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leuk Res. 2007;31:507–514.
170. Atwal KS, Wang P, Rogers WL, et al. Synthesis and biological activity of 5-aryl-4-(4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidine analogs as potent, highly selective, and orally bioavailable NHE-1 inhibitors. Bioorg Med Chem Lett. 2006;16:4796–4799.
171. Kohno K, Ohno S, Eguchi H, et al. Anti-inflammatory and immunomodulatory properties of 2-amino-3H-phenoxazin-3-one. Biol Pharm Bull. 2008;31:1938–1945.
172. 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;71:3364–3376.
173. Supuran CT. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites. 2017;7.
174. Nocentini A, Supuran CT. Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: a patent review (2008–2018). Expert Opin Ther Pat. 2018;28:729–740.
175. Berrino E, Supuran CT. Novel approaches for designing drugs that interfere with pH regulation. Expert Opin Drug Discov. 2019;14:231–248.
176. Bartoov M, Sibony M, Yoles I, et al. Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2. J Pathol. 2002;197:314–321.
177. Chen Q, Lu H, Liu Y, et al. Increased NHE1 expression is targeted by specific inhibitor cariporide to sensitize resistant breast cancer cells to doxorubicin in vitro and in vivo. BMC Cancer. 2019;19:211.
178. Mboge MY, Mahon BP, Lamas N, et al. Selective inhibition of carbonic anhydrase IX over carbonic anhydrase XII in breast cancer cells using benzene sulfonamides: Disconnect between activity and growth inhibition. PLoS One. 2018;13:e0207417.
179. Al Tameemi W, Dale TP, Al-Jumaily RMK, Forsyth NR. Hypoxia-Modified Cancer Cell Metabolism. Front Cell Dev Biol. 2019;7:426290.
180. Long Y, Li Q, Zhong S, et al. Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma. Cancer Med. 2018;7:4690.
181. Spugnini EP, Citro G, Fais S. Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. J Exp Clin Cancer Res. 2010;29:44.
182. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther. 2006;23:2–8.
183. Shin JM, Sachs G. Pharmacology of Proton Pump Inhibitors. Curr Gastroenterol Rep. 2008;10:528.
184. Shin JM, Kim N. Pharmacokinetics and Pharmacodynamics of the Proton Pump Inhibitors. J Neurogastroenterol Motil. 2013;19:25.
185. Lu ZN, Tian B, Guo XL. Repositioning of proton pump inhibitors in cancer therapy. Cancer Chemother Pharmacol. 2017;80:925–937.
186. Wang BY, Zhang QL, Jiang Y, 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.
187. Wang X, Chi J, Zhao Q, et al. Proton pump inhibitors increase the chemosensitivity of patients with advanced colorectal cancer. Oncotarget. 2017;8:58801–58808.
188. Fais S, Venturi G, Gatenby B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev. 2014;33:1095–1108.
189. Erra Díaz F, Dantas E, Geffner J. Unravelling the Interplay between Extracellular Acidosis and Immune Cells. Mediators Inflamm. 2018;2018.
190. Garlatti V, Bellima N, Gaboriaud C, et al. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem. 2007;282:35814–35820.
191. Lardner A. The effects of extracellular pH on immune function. J Leukoc Biol. 2001;69:522–530.
192. Roma-Rodrigues C, Mendes R, Baptista P, Fernandes A. Targeting Tumor Microenvironment for Cancer Therapy. Int J Mol Sci. 2019;20:840.
193. Lim B, Woodward WA, Wang X, Reuben JM, Ueno NT. Inflammatory breast cancer biology: the tumour microenvironment is key. Nat Rev Cancer. 2018;18:485–499.
194. Hoang BX, Shaw DG, Han B, Fang JY, Nimni M. Acidosis and Formaldehyde Secretion as a Possible Pathway of Cancer Pain and Options for Improved Cancer Pain Control. J Pain Palliat Care Pharmacother. 2015;29:276–280.
195. Tvingsholm SA, Dehlendorff C, Østerlind K, Friis S, Jäättelä M. Proton pump inhibitor use and cancer mortality. Int J Cancer. 2018;143:1315–1326.
196. Keizer HG, Joenje H. Increased cytosolic pH in multidrug-resistant human lung tumor cells: effect of verapamil. J Natl Cancer Inst. 1989;81:706–709.
197. Swietach P, Hulikova A, Patiar S, Vaughan-Jones RD, Harris AL. Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS One. 2012;7:e35949.
198. Roepe PD. pH and Multidrug Resistance. Novartis Found Symp. 2001;240:232–250.
199. Reshkin SJ, Bellizzi A, Albarani V, et al. Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. Clin Cancer Res. 2003;9:2366–2373.
200. Dasari S, Bernard Tchounwou P. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–378.
201. Makovec T. Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol. 2019;53:148–158.
202. Chen Z, Thiessen N, Wang W, et al. Differential expression and function of CAIX and CAXII in breast cancer: A comparison between tumorgraft models and cells. PLoS One. 2018;13:e0199476.
203. Lloyd MC, Alfarouk KO, Verduzco D, et al. Vascular measurements correlate with estrogen receptor status. BMC Cancer. 2014;14:279.
204. Hill SM, Belancio VP, Dauchy RT, et al. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer. 2015;22:R183–R204.
205. Moretti E, Favero G, Rodella LF, Rezzani R. Melatonin's Antineoplastic Potential Against Glioblastoma. Cells. 2020;9.
206. Nooshinfar E, Safaroghli-Azar A, Bashash D, Akbari ME. Melatonin, an inhibitory agent in breast cancer. Breast Cancer. 2017;24:42–51.
207. Alvarez-García V, González A, Alonso-González C, Martínez-Campa C, Cos S. Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J Pineal Res. 2013;54:373–380.
208. Lacerda JZ, Privilegio Lopes BR, Aristizabal Prada ET, et al. Therapeutic Potential of Melatonin in the Regulation of MiR-148a-3p and Angiogenic Factors in Breast Cancer. MicroRNA (Shariqah, United Arab Emirates). 2019;8:237–247.
209. Victorasso Jardim-Perassi B, Arbab AS, Ferreira LC, et al. Melatonin Regulates Angiogenic Factors under Hypoxia in Breast Cancer Cell Lines. Anticancer Agents Med Chem. 2016;16:347–358.
210. Reiter RJ, Rosales-Corral S, Tan DX, et al. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci. 2017;18.
211. Sanchez-Sanchez AM, Antolin I, Puente-Moncada N, et al. Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells. PLoS One. 2015;10.
212. Salvati A, Cardone RA, Greco MR, et al. Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer. Int J Mol Sci. 2020;21:1–20.
213. Hasan M, Carter M, Chen C, et al. Pharmacological, mechanistic, and pharmacokinetic assessment of novel_ melatonin-tamoxifen drug conjugates as breast cancer drugs. Mol Pharmacol. 2019;96:272–296.
214. Melnik S, Dvornikov D, Müller-Decker K, et al. Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification. Cell Discov. 2018;4.
215. Bayraktar S, Hernadez-Aya LF, Lei X, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer. 2012;118:1202–1211.
216. 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.
217. Brahimi-Horn C, Pouysségur J. The role of the hypoxia-inducible factor in tumor metabolism growth and invasion. Bull Cancer. 2006;93:E73-E80.
218. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat. 2011;126:355–364.
219. Lv Y, Zhao S, Han J, et al. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer. Onco Targets Ther. 2015;8:1941.
220. Samanta D, Gilkes DM, Chaturvedi P, Xiang L, Semenza GL. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci. 2014;111.
221. Marchiq I, Pouysségur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. J Mol Med. 2016;94:155–171.
222. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441:437–443.
223. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33:207–214.
224. Hsu CW, Shou D, Huang R, et al. Identification of approved and investigational drugs that inhibit hypoxia-inducible factor-1 signaling. Oncotarget. 2016;7:8172–8183.
225. Xu R, Wang F, Yang H, Wang Z. Action Sites and Clinical Application of HIF-1α Inhibitors. Molecules. 2022;27:3426.
226. Brown MR, Bhatt DL, Steg PG, et al. Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes. J Clin Invest. 2021;131.
227. Ch'En FF, Villafuerte FC, Swietach P, Cobden PM, Vaughan‐Jones RD. S0859, an N ‐cyanosulphonamide inhibitor of sodium‐bicarbonate cotransport in the heart. Br J Pharmacol. 2008;153:972–982.
228. Kharb R, Haider K, Neha K, Yar MS. Aromatase inhibitors: Role in postmenopausal breast cancer. Arch Pharm (Weinheim). 2020;353.
229. Nelson M, Yang M, Dowle AA, Thomas JR, Brackenbury WJ. The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis. Mol Cancer. 2015;14:13.
230. Spugnini EP, Fais S. Drug repurposing for anticancer therapies. A lesson from proton pump inhibitors. Expert Opin Ther Pat. 2020;30:15–25.
231. Wu KH, Ho CT, Chen ZF, et al. The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter. J Food Drug Anal. 2018;26:221–231.
232. Bai F, Liu Y, Tu TT, et al. Simvastatin induces breast cancer cell death through oxidative stress up-regulating miR-140-5p. Aging (Albany NY). 2019;11:3198–3219.
233. Wang YC, Morrison G, Gillihan R, et al. Drug Screening Identifies Niclosamide as an Inhibitor of Breast Cancer Stem-Like Cells. PLoS One. 2013;8:e74538.
234. Pronzato P, Campora E, Amoroso D, et al. Phase II study of lonidamine in metastatic breast cancer. Br J Cancer. 1989;59:251–253.
235. Bougnoux P, Hajjaji N, Ferrasson MN, et al. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer. 2009;101:1978–1985.
236. Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012. doi:10.1155/2012/950658.
237. Di Pompo G, Salerno M, Rotili D, et al. Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma. Oncotarget. 2017;8:54478–54496.
238. Evans RJ. Acid-base changes in patients with intractable pain and malignancy. Can J Surg. 1972;15:37–42.
239. Hoang BX, Tran HQ, Vu UV, Pham QT, Shaw DG. Palliative treatment for advanced biliary adenocarcinomas with combination dimethyl sulfoxide-sodium bicarbonate infusion and S-adenosyl-L-methionine. J Pain Palliat Care Pharmacother. 2014;28:206–211.
240. Hoang BX, Han B, Shaw DG, et al. Dimethyl sulfoxide and sodium bicarbonate in the treatment of refractory cancer pain. J Pain Palliat Care Pharmacother. 2011;25:19–24.
241. Hoang BX, Han B, Shaw DG, et al. Dimethyl Sulfoxide--Sodium Bicarbonate Infusion for Palliative Care and Pain Relief in Patients With Metastatic Prostate Cancer. J Pain Palliat Care Pharmacother. 2011;25:350–355.
242. Salim AS. Oxygen-Derived Free-Radical Scavengers Prolong Survival in Colonic Cancer. Chemotherapy. 1992;38:127–134.
243. Voss NCS, Arendt-Nielsen L, Bech M, et al. Targeting the Acidic Tumor Microenvironment: Unexpected Pro-Neoplastic Effects of Oral NaHCO3 Therapy in Murine Breast Tissue. Cancers (Basel). 2020;12:891.
244. Pecorino L. The Molecular Biology of Cancer Mechanism, Target, and Therapeutics. 2012. Publisher: Oxford University Press.
245. Halma MTJ, Tuszynski JA, Marik PE. Cancer Metabolism as a Therapeutic Target and Review of Interventions. Nutrients. 2023;15.
246. Kuhn TS. The Structure of Scientific Revolutions. 2012. The University of Chicago Press.
247. Harguindey, S. Altered and expanded states of consciousness in highly creative human beings. The call of vocation in medicine and science. From perennial philosophy to modern science, psychology, medicine and oncology. Medical Research Archives, 2026. 14(3), 1-20.
2. Chen C, Wang X, Yang T, et al.The pH perspective of cancer: From Warburg's misconception to therapeutic targeting of pH regulating proteins. Crit Rev Oncol Hematol. 2026;217:105051. doi:10.1016/j.critrevon c.2025.105051.
3. Harguindey S. Use of Na+/H+ antiporter inhibitors as a novel approach to cancer treatment. In: Simchowitz EJ, ed. Amiloride and Its Analogs: Unique Cation Transport Inhibitors. New York; 1992:317–334.
4. Harguindey S, Reshkin SJ. The new pH-centric anticancer paradigm in Oncology and Medicine; SCB, 2017. Semin Cancer Biol. 2017;43:1–4.
5. Celi, A.B., Mechali, A., Beltramone, N. et al. Targeting pH regulation in cancer: combined mild alkaline treatment and NHE1 inhibition as a potential therapy for clear cell renal cell carcinoma. Mol Cell Biochem 481, 1875–1887 (2026). https://doi.org/10.1007/s11010-026-05511-3).
6. Schwartz L, Buhler L, Icard P, et al. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014;34:973–980.
7. Harguindey S, Orive G, Cacabelos R, et al. An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs) and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS). Neuropsychiatr Dis Treat. 2008;4:1073–1084.
8. Harguindey S, Alfarouk K, Orozco JP, et al. Hydrogen Ion Dynamics as the Fundamental Link between Neurodegenerative Diseases and Cancer: Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis on Multiple Sclerosis. Int J Mol Sci. 2022;23 (5). https://doi.org/10.3390/ijms23052454
9. Fang B, Wang D, Huang M, Yu G, Li H. Hypothesis on the relationship between the change in intracellular pH and incidence of sporadic Alzheimer's disease or vascular dementia. Int J Neurosci. 2010;120:591–595.
10. Schwartz L, Peres S, Jolicoeur M, da Veiga Moreira J. Cancer and Alzheimer's disease: intracellular pH scales the metabolic disorders. Biogerontology. 2020;21:683–694.
11. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
12. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
13. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12:31–46.
14. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314.
15. Harguindey S, Reshkin SJ, Alfarouk KO. The Prime and Integral Cause of Cancer in the Post-Warburg Era. Cancers (Basel). 2023;15.
16. Harguindey S, Reshkin SJ, Devesa J, et al. The Oncoming Hydrogen Era and The New Paradigm of Cancer and Neurodegenerative Diseases Based on the Hydrogen Ion Dynamics on Cellular Homeostasis and Metabolism - from Etiopathogenesis to Treatment. Medical Research Archives 2026, 14, 3, 1-4. doi: https://doi.org/10.18103/mra.v14i1.7161
17. Harguindey SS, Kolbeck RC, Bransome ED. Letter: Ureterosigmoidostomy and cancer: new observations. Ann Intern Med. 1975;83:833.
18. Harguindey S. Hydrogen ion dynamics and cancer: An appraisal. Med Pediatr Oncol. 1982;10:217–236.
19. Orive G, Reshkin SJ, Harguindey S, Pedraz JL. Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis. Br J Cancer. 2003;89:1395–1399.
20. Huber V, De Milito A, Harguindey S, et al. Proton dynamics in cancer. J Transl Med. 2010;8:57.
21. Harguindey S, Orozco JP, Alfarouk KO, Devesa J. Hydrogen ion dynamics of cancer and a new molecular, biochemical and metabolic approach to the etiopathogenesis and treatment of brain malignancies. Int J Mol Sci. 2019;20. doi:10.3390/ijms20174278.
22. Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ. 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.
23. Harguindey S, Stanciu D, Devesa J, et al. Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases. Semin Cancer Biol. 2017;43: 157–179.
24. Nagata H, Che XF, Miyazawa K, et al. Rapid decrease of intracellular pH associated with inhibition of Na+/H+ exchanger precedes apoptotic events in the MNK45 and MNK74 gastric cancer cell lines treated with 2-aminophenoxazine-3-one. Oncol Rep. 2011;25:341–346.
25. Quach CHT, Kim HD, Coomber BL, et al. Mild Alkalization Acutely Triggers the Warburg Effect by Enhancing Hexokinase Activity via Voltage-Dependent Anion Channel Binding. PLoS One. 2016;11:e0159529.
26. Alfarouk KO, Muddathir AK, Shayoub MEA, 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.
27. 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;14:2185–2197.
28. Grillo-Hill BK, Choi C, Jimenez-Vidal M, Barber DL. Increased H+ efflux is sufficient to induce dysplasia and necessary for viability with oncogene expression. Elife. 2015;4.
29. Amith SR, Wilkinson JM, Fliegel L. Assessing Na+/H+ exchange and cell effector functionality in metastatic breast cancer. Biochim Open. 2016;2:16–23.
30. Liu Y, White KA, Barber DL, et al. Intracellular pH dynamics regulates intestinal stem cell lineage specification. Nat Commun. 2023;14:1–18.
31. Perona R, Portillo F, Giraldez F, Serrano R. Transformation and pH homeostasis of fibroblasts expressing yeast H(+)-ATPase containing site-directed mutations. Mol Cell Biol. 1990;10:4110.
32. Harguindey S, Alfarouk K, Polo Orozco J, et al. A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer Based upon Its Hydrogen Ion Dynamics. Int J Mol Sci. 2020;21:1110.
33. Harguindey S, Arranz JL, Wahl ML, Orive G, Reshkin SJ. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res. 2009;29:2127–2136.
34. Schwartz L, Seyfried T, Alfarouk KO, et al. Out of Warburg effect: An effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin Cancer Biol. 2017;43:134–138.
35. Greco MR, Fracasso F, Cannone S, et al. Acidosis Drives Vasculogenic Mimicry in PDAC CSCs via Na+/H+ Exchanger Isoform 1 (NHE1) and Calcium Entry. Cells. 2026; 15(10):865. https://doi.org/10.3390/cells15100865
36. Koltai T, Reshkin SJ, Baltazar F, Fliegel L. Prostate Cancer Metabolism. In: Prostate Cancer Metabolism: From Biochemistry to Therapeutics. Elsevier; 2021. doi:10.1016/C2020-0-03559-0.
37. Harguindey S, Henderson ES, Naeher C. Effects of systemic acidification of mice with Sarcoma 180. Cancer Res. 1979;39:4364–4371.
38. Hippocrates. On Airs, Waters, and Places. The Internet Classics Archive.
http://classics.mit.edu/Hippocrates/airwatpl.html.
39. Parks SK, Chiche J, Pouysségur J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer. 2013;13:611–623.
40. Kroemer G, Pouyssegur J. Tumor Cell Metabolism: Cancer's Achilles' Heel. Cancer Cell. 2008;13:472–482. doi:10.1016/j.ccr.2008.05.005.
41. Alfarouk KO, Muddathir AK, Shayoub MEA. Tumor acidity as evolutionary spite. Cancers (Basel). 2011;3: 408–414.
42. Huber V, Camisaschi C, Berzi A, et al. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol. 2017;43:74–89.
43. Cannon WB. Organization for Physiological Homeostasis. Physiol Rev. 1929;9:399–431.
44. Selye H. The evolution of the stress concept. Am Sci. 1973;61:692–699.
45. Harguindey S, Katin M, Edgerton F, Takita H. Hierarchical organization, integrations in biology and cancer, balance loss, and a question on modernism. Med Hypotheses. 1981;7:1123–1132.
46. Rauch C, Braet F, Thome L, et al. Cell Membranes, Cytosolic pH and Drug Transport in Cancer and MDR: Physics, Biochemistry and Molecular Biology. Mult Drug Resist. 2009;0044:1–24.
47. Cone C. D. Unified theory on the basic mechanism of normal mitotic control and oncogenesis J Theor biol 1971,30,151-181.
48. An J, Zhang L, Duan Y, Pu S, Peng F. Sodium's role and therapeutic targeting in cancer. Trends Pharmacol Sci. 2026 Jan;47(1):53-65. doi: 10.1016/j.tips.2025.10.015. Epub 2025 Nov 28. PMID: 41318248.)
49. Lim H, Albatany M, Martínez-Santiesteban F, Bartha R, Scholl TJ. Longitudinal Measurements of Intra- and Extracellular pH Gradient in a Rat Model of Glioma. Tomography. 2018;4:46.
50. Honasoge A, Sontheimer H. Involvement of tumor acidification in brain cancer pathophysiology. Front Physiol. 2013;4.
51. di Cristofori A, Carrabba G, Faou P, et al. The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma. Oncotarget. 2015;6:17514–17531.
52. Spugnini EP, Sonveaux P, Stock C, et al. Proton channels and exchangers in cancer. Biochim Biophys Acta - Biomembr. 2014;1848:2715–2726.
53. Perek N, Denoyer D, Dubois F, Koumanov F. Malignant gliomas display altered plasma membrane potential and pH regulation--interaction with Tc-99m-MIBI and Tc-99m-Tetrofosmin uptakes. Gen Physiol Biophys. 2002;21:381–404.
54. Luciani F, Spada M, De Milito A, et al. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst. 2004;96:1702–1713.
55. Mboge MY, Mahon BP, McKenna R, Frost SC. Carbonic Anhydrases: Role in pH Control and Cancer. Metabolites. 2018;8:19.
56. Shirmanova MV, Druzhkova IN, Lukina MM, et al. Chemotherapy with cisplatin: insights into intracellular pH and metabolic landscape of cancer cells in vitro and in vivo. Sci Rep. 2017;7:8911.
57. Miranda-Goncalves V, Reis RM, Baltazar F. Lactate Transporters and pH Regulation: Potential Therapeutic Targets in Glioblastomas. Curr Cancer Drug Targets. 2016;16:388–399.
58. Raudenska M, Balvan J, Fojtu M, Gumulec J, Masarik M. Unexpected therapeutic effects of cisplatin. Metallomics. 2019;11:1182–1199.
59. Tamtaji OR, Mirzaei H, Reiter RJ, et al. New trends in glioma cancer therapy: Targeting Na+ /H + exchangers. J Cell Physiol. 2020;235:658–665.
60. Guan X, Luo L, Sun W, et al. Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas. J Exp Clin Cancer Res. 2018;37.
61. Omran Z, Scaife P, Stewart S, Rauch C. Physical and biological characteristics of multi drug resistance (MDR): An integral approach considering pH and drug resistance in cancer. Semin Cancer Biol. 2017;43:42–48.
62. Zhu W, Carney KE, Pigott VM, et al. Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1. Carcinogenesis. 2016;37:839–851.
63. Reshkin SJ, Cardone RA, Harguindey S. Na+-H+ exchanger, pH regulation and cancer. Recent Pat Anticancer Drug Discov. 2013;8:85–99.
64. Cardone RA, Casavola V, Reshkin SJ. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer. 2005;5:786–795.
65. Bellone M, Calcinotto A, Filipazzi P, et al. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology. 2013;2.
66. Lacroix R, Rozeman EA, Kreutz M, Renner K, Blank CU. Targeting tumor-associated acidity in cancer immunotherapy. Cancer Immunol Immunother. 2018;67:1331–1348.
67. Thews O, Riemann A. Tumor pH and metastasis: a malignant process beyond hypoxia. Cancer Metastasis Rev. 2019;38:113–129.
68. Harguindey S, Koltai T, Reshkin SJ. Curing cancer? Further along the new pH-centric road and paradigm. Oncoscience. 2018;5:132.
69. Albatany M, Li A, Meakin S, Bartha R. In vivo detection of acute intracellular acidification in glioblastoma multiforme following a single dose of cariporide. Int J Clin Oncol. 2018;23:812–819.
70. Aggarwal M, Kondeti B, McKenna R. Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review. Expert Opin Ther Pat. 2013;23:717–724.
71. Pillai SR, Damaghi M, Marunaka Y, et al. Causes, consequences, and therapy of tumors acidosis. Cancer Metastasis Rev. 2019;38:205–222.
72. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, et al. Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy. Cancer Res. 2016;76:1381–1390.
73. Calcinotto A, Filipazzi P, Grioni M, et al. Modulation of Microenvironment Acidity Reverses Anergy in Human and Murine Tumor-Infiltrating T Lymphocytes. Cancer Res. 2012;72:2746–2756.
74. Martin NK, Robey IF, Gaffney EA, et al. Mathematical Biosciences A mathematical model of tumour and blood pHe regulation: The HCO À buffering system. Math Biosci. 2011;230:1–11.
75. Dighe A, Kulkarni S, Srivastava A, et al. Experimental and phylogenetic evidence for correlated gene expression evolution in endometrial and skin fibroblasts. iScience. 2024;27:108593.
76. Meads MB, Gatenby RA, Dalton WS. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer. 2009;9:665–674.
77. Robey IF, Baggett BK, Kirkpatrick ND, et al. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res. 2009;69:2260–2268.
78. Gatenby RA, Gillies RJ. A microenvironmental model of carcinogenesis. Nat Rev Cancer. 2008;8:56–61.
79. Moellering RE, Black KC, Krishnamurty C, et al. Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis. 2008;25:411–425.
80. Gatenby RA, Smallbone K, Maini PK, et al. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer. 2007;97:646–653.
81. Rich IN, Worthington-White D, Garden OA, Musk P. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood. 2000;95:1427–1434.
82. Nijhout HF. Metaphors and the role of genes in development. Bioessays. 1990;12:441–446.
83. Colen CB, Shen YM, Ghoddoussi F, et al. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia. 2011;13:620–632.
84. Geeviman K, Babu D, Prakash Babu P. Pantoprazole Induces Mitochondrial Apoptosis and Attenuates NF-κB Signaling in Glioma Cells. Cell Mol Neurobiol. 2018;38:1491–1504.
85. 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.
86. Harley W, Floyd C, Bhatt T, et al. Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas. Brain Res. 2010. doi:10.1016/j.brainres.2010.09.059.
87. Marathe K, McVicar N, Li A, et al. Topiramate induces acute intracellular acidification in glioblastoma. J Neurooncol. 2016;130:465–472.
88. Albatany M, Meakin S, Bartha R. The Monocarboxylate transporter inhibitor Quercetin induces intracellular acidification in a mouse model of Glioblastoma Multiforme: in-vivo detection using magnetic resonance imaging. Invest New Drugs. 2019;37:595–601.
89. Albatany M, Ostapchenko VG, Meakin S, Bartha R. Brain tumor acidification using drugs simultaneously targeting multiple pH regulatory mechanisms. J Neurooncol. 2019;144: 453–462.
90. Pérez-Escuredo J, Van Hée VF, Sboarina M, et al. Monocarboxylate transporters in the brain and in cancer. Biochim Biophys Acta. 2016;1863:2481–2497.
91. Miranda-Gonçalves V, Honavar M, Pinheiro C, et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro Oncol. 2013;15:172–188.
92. Anemone A, Consolino L, Arena F, Capozza M, Longo DL. Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH. Cancer Metastasis Rev. 2019;38:25–49.
93. Koltai T. Triple-edged therapy targeting intracellular alkalosis and extracellular acidosis in cancer. Semin Cancer Biol. 2017;43:139–146.
94. Chirasani SR, Leukel P, Gottfried E, et al. Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. Int J Cancer. 2013;132:843–853.
95. Binello E, Germano IM. Targeting glioma stem cells: a novel framework for brain tumors. Cancer Sci. 2011;102:1958–1966.
96. Gdovin MJ, Kadri N, Rios L, Holliday S, Jordan Z. Focal photodynamic intracellular acidification as a cancer therapeutic. Semin Cancer Biol. 2017;43:147–156.
97. Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm. 2015;93:52–79.
98. Kusuzaki K, Matsubara T, Murata H, et al. Natural extracellular nanovesicles and photodynamic molecules: is there a future for drug delivery? J Enzyme Inhib Med Chem. 2017;32:908–916.
99. Litan A, Langhans SA. Cancer as a channelopathy: ion channels and pumps in tumor development and progression. Front Cell Neurosci. 2015;9.
100. Besson P, Roger S, Neuhart S, et al. How do voltage-gated sodium channels enhance migration and invasiveness in cancer cells? Biochim Biophys Acta. 2015;1848:2493–2501.
101. Brackenbury WJ, Palmieri C. Blocking channels to metastasis: targeting sodium transport in breast cancer. Breast Cancer Res. 2023;25:1–3.
102. Purow B. Repurposing existing agents as adjunct therapies for glioblastoma. Neuro-Oncology Pract. 2016;3:154.
103. Harguindey S, Alfarouk K, Polo Orozco J, et al. Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era. Int J Mol Sci. 2020;21:7475.
104. Koltai T, Reshkin SJ, Harguindey S. An Innovative Approach to Understanding and Treating Cancer: Targeting PH From Etiopathogenesis to New Therapeutic Avenues. In: An Innovative Approach to Understanding and Treating Cancer: Targeting pH. Amsterdam: Elsevier; 2020. doi:10.1016/C2018-0-02687-0.
105. Egger SJ, Willson ML, Morgan J, et al. Platinum-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2017;6.
106. Cardone RA, Greco MR, Capulli M, et al. The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela. Int J Mol Sci. 2019;20:3694.
107. Alfarouk KO, Verduzco D, Rauch C, et al. The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer. Cancers (Basel). 2020;12:898.
108. Alfarouk KO, Stock CM, Taylor S, et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int. 2015;15:71.
109. Amith SR, Fliegel L. Na+/H+ exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics. Semin Cancer Biol. 2017;43:35–41.
110. Amith SR, Fliegel L. Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis. Cancer Res. 2013;73:1259–1264.
111. Lobo RC, Bhatt DL, Fan C, et al. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity. Front Cell Dev Biol. 2016;4.
112. Fliegel L. Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer. Rev Physiol Biochem Pharmacol. 2022;182:85–110.
113. Ma Z, Myers DP, Wu RF, et al. Function of ion transporters in maintaining acid-base homeostasis of the mammary gland and the pathophysiological role in breast cancer. Am J Physiol Regul Integr Comp Physiol. 2020;318:R98–R111.
114. Lee S, Axelsen TV, Andersen AP, et al. Na+,HCO3 − cotransport is functionally upregulated during human breast carcinogenesis and required for the inverted pH gradient across the plasma membrane. Pflügers Arch - Eur J Physiol. 2015;467:367–377.
115. Andersen AP, Sander LK, Kveiborg M, et al. The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms. Int J Cancer. 2018;142:2529–2542.
116. Boedtkjer E, Bunch L, Pedersen SF, et al. Contribution of Na+,HCO3(-)-cotransport to cellular pH control in human breast cancer: A role for the breast cancer susceptibility locus NBCn1 (SLC4A7). Int J Cancer. 2013; 132:1288–1299.
117. Pinheiro C, Longatto-Filho A, Ferreira L, et al. GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol. 2011;26:1279–1286.
118. Brisson L, Driffort V, Benoist L, et al. Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H(+) efflux in caveolae. Oncogene. 2011;30:2070–2076.
119. Fraser SP, Diss JK, Lloyd LJ, et al. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clin Cancer Res. 2005;11:5381–5389.
120. Cotter K, Capecci J, Martinez-Zaguilan R, et al. The a3 isoform of subunit a of the vacuolar ATPase localizes to the plasma membrane of invasive breast tumor cells and is overexpressed in human breast cancer. Oncotarget. 2016;7:46142–46157.
121. 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;1832:606–617.
122. von Schwarzenberg K, Lajber M, Vollmar AM, et al. V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. Mol Oncol. 2014;8:9–19.
123. Yu C, Chen X, Lin Y, et al. Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect. Oncotarget. 2017;8:83831–83844.
124. Amith SR, Fong S, Baksh S, Fliegel L. Na (+)/H (+)exchange in the tumor microenvironment: does NHE1 drive breast cancer carcinogenesis? Int J Dev Biol. 2015;59:367–377.
125. Zheng T, Jäättelä M, Liu B. pH gradient reversal fuels cancer progression. Int J Biochem Cell Biol. 2020; 125.
126. Mihaila RG. A minireview on NHE1 inhibitors. A rediscovered hope in oncohematology. Biomed Pap. 2015;159:519–526.
127. Flinck M, Kramer SH, Schnipper J, Andersen AP, Pedersen SF. The acid-base transport proteins NHE1 and NBCn1 regulate cell cycle progression in human breast cancer cells. Cell Cycle. 2018;17:1056–1067.
128. Lee S, Axelsen TV, Jessen N, et al. Disrupting Na+, HCO₃−-cotransporter NBCn1 (Slc4a7) delays murine breast cancer development. Oncogene. 2016;35:2112–2122.
129. Baenke F, Murillo-Garzon V, Norkin M, et al. Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival. J Pathol. 2015;237:152–165.
130. Goh W, Sleptsova-Freidrich I, Petrovic N. Use of proton pump inhibitors as adjunct treatment for triple-negative breast cancers. An introductory study. J Pharm Pharm Sci. 2014;17:439–446.
131. Morais-Santos F, Miranda-Gonçalves V, Pinto-Gomes S, et al. Targeting lactate transport suppresses in vivo breast tumour growth. Oncotarget. 2015;6:19177–19189.
132. Pinheiro C, Reis RM, Ricardo S, et al. Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology. 2010;56:860–867.
133. Boedtkjer E. Na+,HCO3- cotransporter NBCn1 accelerates breast carcinogenesis. Cancer Metastasis Rev. 2019;38:165–178.
134. Toft NJ, Axelsen TV, Pedersen HL, et al. Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival. Elife. 2021;10.
135. Yang M, Kozminski DJ, Wold LA, et al. Therapeutic potential for phenytoin: targeting Nav1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat. 2012;134: 603–615.
136. O'Grady S, Morgan MP, O'Grady S, Morgan MP. Calcium transport and signalling in breast cancer: Functional and prognostic significance. Semin Cancer Biol. 2021;72:19–26.
137. Kruger LC, Isom LL. Voltage-Gated Na+ Channels: Not Just for Conduction. Cold Spring Harb Perspect Biol. 2016;8:a029264.
138. Hernandez CM, Richards JR. Physiology, Sodium Channels. StatPearls. 2024.
139. Nelson M, Yang M, Millican-Slater R, Brackenbury WJ. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo. Oncotarget. 2015;6:32914–32929.
140. Dowd J, Hendin J, Fukushiro-Lopes DF, Laczynski D, Gentile S. Ion Channels in Breast Cancer: From Signaling to Therapy. In: Breast Cancer - From Biology to Medicine. InTech; 2017. doi:10.5772/66172.
141. Dhakan C, Anemone A, Ventura V, et al. Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging---Chemical Exchange Saturation Transfer Tumor pH Imaging. Metabolites. 2023;13:1161.
142. Ibrahim-Hashim A, Estrella V. Acidosis and Cancer: from Mechanism to Neutralization. Cancer Metastasis Rev. 2019;38:149.
143. Böhme I, Bosserhoff A. Extracellular acidosis triggers a senescence‐like phenotype in human melanoma cells. Pigment Cell Melanoma Res. 2020;33:41–51.
144. Germain D. Estrogen Carcinogenesis in Breast Cancer. Endocrinol Metab Clin North Am. 2011;40:473–484.
145. Meehan J, Ward C, Turnbull AK, et al. Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells. Oncotarget. 2017;8:42857–42875.
146. Kaloyianni M, Bourikas D, Koliakos G. The effect of insulin on Na+-H+ antiport activity of obese and normal subjects erythrocytes. Cell Physiol Biochem. 2001;11:253–258.
147. Moore RD, Gupta RK. Effect of insulin on intracellular ph as observed by 31p NMR spectroscopy. Int J Quantum Chem. 2009;18:83–92.
148. Williams B, Howard RL. Glucose-induced changes in Na+/H+ antiport activity and gene expression in cultured vascular smooth muscle cells. Role of protein kinase C. J Clin Invest. 1994;93:2623–2631.
149. Ramírez MA, Zavala AV, del Valle Lepez M, et al. Involvement of Intracellular pH in Vascular Insulin Resistance. Curr Vasc Pharmacol. 2019;17:440–446.
150. Lann D, LeRoith D. The role of endocrine insulin-like growth factor-I and insulin in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:371–379.
151. Gunter MJ, Hoover DR, Yu H, et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2009;101:48–60.
152. Clevenger CV, Furth PA, Hankinson SE, Schuler LA. The role of prolactin in mammary carcinoma. Endocr Rev. 2003;24:1–27.
153. Pedraz-Cuesta E, Christensen ST, Vendel Nielsen L, et al. Prolactin Signaling Stimulates Invasion via Na(+) /H(+) exchanger NHE1 in T47D Human Breast Cancer Cells. Mol Endocrinol. 2016. doi:10.1210/me.2015-1299.
154. Wennbo H, Gebre-Medhin M, Gritli-Linde A, et al. Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest. 1997;100:2744.
155. Koedoot E, Bost M, Sahai E, et al. Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes. Nat Commun. 2019;10:1–16.
156. Tavares-Valente D, Baltazar F, Moreira R, Queirós O. Cancer cell bioenergetics and pH regulation influence breast cancer cell resistance to paclitaxel and doxorubicin. J Bioenerg Biomembr. 2013;45:467–475.
157. Thews O, Gassner B, Kelleher DK, Schwerdt G, Gekle M. Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia. 2006;8:143–152.
158. Roepe PD, Wei LY, Cruz J, Carlson D. Lower electrical membrane potential and altered pHi homeostasis in multidrug-resistant (MDR) cells: further characterization of a series of MDR cell lines expressing different levels of P-glycoprotein. Biochemistry. 1993;32:11042–11056.
159. Taylor S, Spugnini EP, Assaraf YG, et al. Microenvironment acidity as a major determinant of tumor chemo-resistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resist Updat. 2015;23:69–78.
160. Barrière H, Bagdany M, Bhatt A, et al. CFTR modulates programmed cell death by decreasing intracellular pH in Chinese hamster lung fibroblasts. Am J Physiol Physiol. 2001;281:C810–C824.
161. Horvat B, Taheri S, Salihagić A. Tumour cell proliferation is abolished by inhibitors of Na+/H+ and HCO3-/Cl- exchange. Eur J Cancer. 1992;29A:132–137.
162. I.L. Cameron, I., L. Intervention of sodium flux as a target for cancer chemo- therapy. In: New Approaches to Cancer Chemotherapy, Academic Press, New York, 1984, pp. 355– 374.
163. Sparks RL, Pool TB, Smith NK, Cameron IL. Effects of amiloride on tumor growth and intracellular element content of tumor cells in vivo. Cancer Res. 1983;43:73–77.
164. Roger S, Besson P, Le Guennec JY. Involvement of a novel fast inward sodium current in the invasion capacity of a breast cancer cell line. Biochim Biophys Acta - Biomembr. 2003;1616:107–111.
165. He B, Zhang M, Zhu R. Na+/H+ exchanger blockade inhibits the expression of vascular endothelial growth factor in SGC7901 cells. Oncol Rep. 2010;23:79–87.
166. Kellen JA, Mirakian A, Kolin A. Antimetastatic effect of amiloride in an animal tumour model. Anticancer Res. 1988;8:1373–1376.
167. Evans DM, Sloan-Stakleff K, Arvan M, Guyton DP. Time and dose dependency of the suppression of pulmonary metastases of rat mammary cancer by amiloride. Clin Exp Metastasis. 1998;16:353–357.
168. Matthews H, Ranson M, Kelso MJ, et al. 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;129:2051–2061.
169. He B, Deng C, Zhang M, Zou D, Xu M. Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leuk Res. 2007;31:507–514.
170. Atwal KS, Wang P, Rogers WL, et al. Synthesis and biological activity of 5-aryl-4-(4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidine analogs as potent, highly selective, and orally bioavailable NHE-1 inhibitors. Bioorg Med Chem Lett. 2006;16:4796–4799.
171. Kohno K, Ohno S, Eguchi H, et al. Anti-inflammatory and immunomodulatory properties of 2-amino-3H-phenoxazin-3-one. Biol Pharm Bull. 2008;31:1938–1945.
172. 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;71:3364–3376.
173. Supuran CT. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites. 2017;7.
174. Nocentini A, Supuran CT. Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: a patent review (2008–2018). Expert Opin Ther Pat. 2018;28:729–740.
175. Berrino E, Supuran CT. Novel approaches for designing drugs that interfere with pH regulation. Expert Opin Drug Discov. 2019;14:231–248.
176. Bartoov M, Sibony M, Yoles I, et al. Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2. J Pathol. 2002;197:314–321.
177. Chen Q, Lu H, Liu Y, et al. Increased NHE1 expression is targeted by specific inhibitor cariporide to sensitize resistant breast cancer cells to doxorubicin in vitro and in vivo. BMC Cancer. 2019;19:211.
178. Mboge MY, Mahon BP, Lamas N, et al. Selective inhibition of carbonic anhydrase IX over carbonic anhydrase XII in breast cancer cells using benzene sulfonamides: Disconnect between activity and growth inhibition. PLoS One. 2018;13:e0207417.
179. Al Tameemi W, Dale TP, Al-Jumaily RMK, Forsyth NR. Hypoxia-Modified Cancer Cell Metabolism. Front Cell Dev Biol. 2019;7:426290.
180. Long Y, Li Q, Zhong S, et al. Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma. Cancer Med. 2018;7:4690.
181. Spugnini EP, Citro G, Fais S. Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. J Exp Clin Cancer Res. 2010;29:44.
182. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther. 2006;23:2–8.
183. Shin JM, Sachs G. Pharmacology of Proton Pump Inhibitors. Curr Gastroenterol Rep. 2008;10:528.
184. Shin JM, Kim N. Pharmacokinetics and Pharmacodynamics of the Proton Pump Inhibitors. J Neurogastroenterol Motil. 2013;19:25.
185. Lu ZN, Tian B, Guo XL. Repositioning of proton pump inhibitors in cancer therapy. Cancer Chemother Pharmacol. 2017;80:925–937.
186. Wang BY, Zhang QL, Jiang Y, 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.
187. Wang X, Chi J, Zhao Q, et al. Proton pump inhibitors increase the chemosensitivity of patients with advanced colorectal cancer. Oncotarget. 2017;8:58801–58808.
188. Fais S, Venturi G, Gatenby B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev. 2014;33:1095–1108.
189. Erra Díaz F, Dantas E, Geffner J. Unravelling the Interplay between Extracellular Acidosis and Immune Cells. Mediators Inflamm. 2018;2018.
190. Garlatti V, Bellima N, Gaboriaud C, et al. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem. 2007;282:35814–35820.
191. Lardner A. The effects of extracellular pH on immune function. J Leukoc Biol. 2001;69:522–530.
192. Roma-Rodrigues C, Mendes R, Baptista P, Fernandes A. Targeting Tumor Microenvironment for Cancer Therapy. Int J Mol Sci. 2019;20:840.
193. Lim B, Woodward WA, Wang X, Reuben JM, Ueno NT. Inflammatory breast cancer biology: the tumour microenvironment is key. Nat Rev Cancer. 2018;18:485–499.
194. Hoang BX, Shaw DG, Han B, Fang JY, Nimni M. Acidosis and Formaldehyde Secretion as a Possible Pathway of Cancer Pain and Options for Improved Cancer Pain Control. J Pain Palliat Care Pharmacother. 2015;29:276–280.
195. Tvingsholm SA, Dehlendorff C, Østerlind K, Friis S, Jäättelä M. Proton pump inhibitor use and cancer mortality. Int J Cancer. 2018;143:1315–1326.
196. Keizer HG, Joenje H. Increased cytosolic pH in multidrug-resistant human lung tumor cells: effect of verapamil. J Natl Cancer Inst. 1989;81:706–709.
197. Swietach P, Hulikova A, Patiar S, Vaughan-Jones RD, Harris AL. Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS One. 2012;7:e35949.
198. Roepe PD. pH and Multidrug Resistance. Novartis Found Symp. 2001;240:232–250.
199. Reshkin SJ, Bellizzi A, Albarani V, et al. Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. Clin Cancer Res. 2003;9:2366–2373.
200. Dasari S, Bernard Tchounwou P. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–378.
201. Makovec T. Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol. 2019;53:148–158.
202. Chen Z, Thiessen N, Wang W, et al. Differential expression and function of CAIX and CAXII in breast cancer: A comparison between tumorgraft models and cells. PLoS One. 2018;13:e0199476.
203. Lloyd MC, Alfarouk KO, Verduzco D, et al. Vascular measurements correlate with estrogen receptor status. BMC Cancer. 2014;14:279.
204. Hill SM, Belancio VP, Dauchy RT, et al. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer. 2015;22:R183–R204.
205. Moretti E, Favero G, Rodella LF, Rezzani R. Melatonin's Antineoplastic Potential Against Glioblastoma. Cells. 2020;9.
206. Nooshinfar E, Safaroghli-Azar A, Bashash D, Akbari ME. Melatonin, an inhibitory agent in breast cancer. Breast Cancer. 2017;24:42–51.
207. Alvarez-García V, González A, Alonso-González C, Martínez-Campa C, Cos S. Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J Pineal Res. 2013;54:373–380.
208. Lacerda JZ, Privilegio Lopes BR, Aristizabal Prada ET, et al. Therapeutic Potential of Melatonin in the Regulation of MiR-148a-3p and Angiogenic Factors in Breast Cancer. MicroRNA (Shariqah, United Arab Emirates). 2019;8:237–247.
209. Victorasso Jardim-Perassi B, Arbab AS, Ferreira LC, et al. Melatonin Regulates Angiogenic Factors under Hypoxia in Breast Cancer Cell Lines. Anticancer Agents Med Chem. 2016;16:347–358.
210. Reiter RJ, Rosales-Corral S, Tan DX, et al. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci. 2017;18.
211. Sanchez-Sanchez AM, Antolin I, Puente-Moncada N, et al. Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells. PLoS One. 2015;10.
212. Salvati A, Cardone RA, Greco MR, et al. Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer. Int J Mol Sci. 2020;21:1–20.
213. Hasan M, Carter M, Chen C, et al. Pharmacological, mechanistic, and pharmacokinetic assessment of novel_ melatonin-tamoxifen drug conjugates as breast cancer drugs. Mol Pharmacol. 2019;96:272–296.
214. Melnik S, Dvornikov D, Müller-Decker K, et al. Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification. Cell Discov. 2018;4.
215. Bayraktar S, Hernadez-Aya LF, Lei X, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer. 2012;118:1202–1211.
216. 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.
217. Brahimi-Horn C, Pouysségur J. The role of the hypoxia-inducible factor in tumor metabolism growth and invasion. Bull Cancer. 2006;93:E73-E80.
218. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat. 2011;126:355–364.
219. Lv Y, Zhao S, Han J, et al. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer. Onco Targets Ther. 2015;8:1941.
220. Samanta D, Gilkes DM, Chaturvedi P, Xiang L, Semenza GL. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci. 2014;111.
221. Marchiq I, Pouysségur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. J Mol Med. 2016;94:155–171.
222. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441:437–443.
223. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33:207–214.
224. Hsu CW, Shou D, Huang R, et al. Identification of approved and investigational drugs that inhibit hypoxia-inducible factor-1 signaling. Oncotarget. 2016;7:8172–8183.
225. Xu R, Wang F, Yang H, Wang Z. Action Sites and Clinical Application of HIF-1α Inhibitors. Molecules. 2022;27:3426.
226. Brown MR, Bhatt DL, Steg PG, et al. Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes. J Clin Invest. 2021;131.
227. Ch'En FF, Villafuerte FC, Swietach P, Cobden PM, Vaughan‐Jones RD. S0859, an N ‐cyanosulphonamide inhibitor of sodium‐bicarbonate cotransport in the heart. Br J Pharmacol. 2008;153:972–982.
228. Kharb R, Haider K, Neha K, Yar MS. Aromatase inhibitors: Role in postmenopausal breast cancer. Arch Pharm (Weinheim). 2020;353.
229. Nelson M, Yang M, Dowle AA, Thomas JR, Brackenbury WJ. The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis. Mol Cancer. 2015;14:13.
230. Spugnini EP, Fais S. Drug repurposing for anticancer therapies. A lesson from proton pump inhibitors. Expert Opin Ther Pat. 2020;30:15–25.
231. Wu KH, Ho CT, Chen ZF, et al. The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter. J Food Drug Anal. 2018;26:221–231.
232. Bai F, Liu Y, Tu TT, et al. Simvastatin induces breast cancer cell death through oxidative stress up-regulating miR-140-5p. Aging (Albany NY). 2019;11:3198–3219.
233. Wang YC, Morrison G, Gillihan R, et al. Drug Screening Identifies Niclosamide as an Inhibitor of Breast Cancer Stem-Like Cells. PLoS One. 2013;8:e74538.
234. Pronzato P, Campora E, Amoroso D, et al. Phase II study of lonidamine in metastatic breast cancer. Br J Cancer. 1989;59:251–253.
235. Bougnoux P, Hajjaji N, Ferrasson MN, et al. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer. 2009;101:1978–1985.
236. Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012. doi:10.1155/2012/950658.
237. Di Pompo G, Salerno M, Rotili D, et al. Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma. Oncotarget. 2017;8:54478–54496.
238. Evans RJ. Acid-base changes in patients with intractable pain and malignancy. Can J Surg. 1972;15:37–42.
239. Hoang BX, Tran HQ, Vu UV, Pham QT, Shaw DG. Palliative treatment for advanced biliary adenocarcinomas with combination dimethyl sulfoxide-sodium bicarbonate infusion and S-adenosyl-L-methionine. J Pain Palliat Care Pharmacother. 2014;28:206–211.
240. Hoang BX, Han B, Shaw DG, et al. Dimethyl sulfoxide and sodium bicarbonate in the treatment of refractory cancer pain. J Pain Palliat Care Pharmacother. 2011;25:19–24.
241. Hoang BX, Han B, Shaw DG, et al. Dimethyl Sulfoxide--Sodium Bicarbonate Infusion for Palliative Care and Pain Relief in Patients With Metastatic Prostate Cancer. J Pain Palliat Care Pharmacother. 2011;25:350–355.
242. Salim AS. Oxygen-Derived Free-Radical Scavengers Prolong Survival in Colonic Cancer. Chemotherapy. 1992;38:127–134.
243. Voss NCS, Arendt-Nielsen L, Bech M, et al. Targeting the Acidic Tumor Microenvironment: Unexpected Pro-Neoplastic Effects of Oral NaHCO3 Therapy in Murine Breast Tissue. Cancers (Basel). 2020;12:891.
244. Pecorino L. The Molecular Biology of Cancer Mechanism, Target, and Therapeutics. 2012. Publisher: Oxford University Press.
245. Halma MTJ, Tuszynski JA, Marik PE. Cancer Metabolism as a Therapeutic Target and Review of Interventions. Nutrients. 2023;15.
246. Kuhn TS. The Structure of Scientific Revolutions. 2012. The University of Chicago Press.
247. Harguindey, S. Altered and expanded states of consciousness in highly creative human beings. The call of vocation in medicine and science. From perennial philosophy to modern science, psychology, medicine and oncology. Medical Research Archives, 2026. 14(3), 1-20.