{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:21:28Z","timestamp":1793089288760,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\u201cDysregulated\u201d metabolism is a characteristic of the cancer cell phenotype. This includes persistent use of glycolytic metabolism in normoxic environments (Warburg effect) leading to increased acid production and accumulation of protons in the interstitial space. Although often thought to be disordered, altered cancer metabolism is the outcome of intense Darwinian selection and, thus, must have evolved to maximize cancer cell fitness. In an evolutionary context, cancer-induced acidification of the microenvironment represents a niche construction strategy to promote proliferation. Ecological advantages conferred on the cancer population included remodeling of the extracellular matrix to promote local invasion, suppression of potential competitive proliferation of fibroblasts, and suppression of host immune response. Preclinical data demonstrates that increasing the serum buffering capacity (through, for example, oral sodium bicarbonate and TRIS) can neutralize the acidic tumor microenvironment with inhibition local invasion and proliferation which can be synergistic with the effects of chemotherapy and immunotherapy agents. Here, we describe the proton dynamics in cancer and their influence on tumor progression and metastasis. Additionally, we will discuss targeting the tumor acidosis with alkalizing agents including our bicarbonate clinical trial results.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:uri>clinicaltrials.gov<\/jats:uri>\n                      , identifier NCT01350583, NCT01198821 and NCT01846429.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2022.981718","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:39:50Z","timestamp":1668386390000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Back to basic: Trials and tribulations of alkalizing agents in cancer"],"prefix":"10.3389","volume":"12","author":[{"given":"Robert J.","family":"Gillies","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arig","family":"Ibrahim-Hashim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce","family":"Ordway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Gatenby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809","article-title":"Understanding the warburg effect: the metabolic requirements of cell proliferation","volume":"324","author":"Vander Heiden","year":"2009","journal-title":"Science."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.8.6.519","article-title":"Uber den stoffwechsel der carcinomzelle","volume":"152","author":"Warburg","year":"1924","journal-title":"Bioichem Z."},{"key":"B3","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/1475-2867-13-89","article-title":"Acidic extracellular microenvironment and cancer","volume":"13","author":"Kato","year":"2013","journal-title":"Cancer Cell Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1522-2594(199904)41:4<743::AID-MRM13>3.0.CO;2-Z","article-title":"In vivo imaging of extracellular pH using 1H MRSI","volume":"41","author":"van Sluis","year":"1999","journal-title":"Magn Reson Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2016.1176394","article-title":"Lysosomal protein relocation as an adaptation mechanism to extracellular acidosis","volume":"15","author":"Damaghi","year":"2016","journal-title":"Cell Cycle"},{"key":"B6","doi-asserted-by":"publisher","first-page":"8752","DOI":"10.1038\/ncomms9752","article-title":"Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane","volume":"6","author":"Damaghi","year":"2015","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3881","article-title":"Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments","volume":"72","author":"Wojtkowiak","year":"2012","journal-title":"Cancer Res"},{"key":"B8","article-title":"Handbook of magnetic resonance spectroscopy","volume-title":"Vivo: MRS theory, practice and applications","author":"Bottomley","year":"2016"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-4193","article-title":"Acid-mediated tumor invasion: a multidisciplinary study","volume":"66","author":"Gatenby","year":"2006","journal-title":"Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1272","article-title":"Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes","volume":"72","author":"Calcinotto","year":"2012","journal-title":"Cancer Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.69.4.522","article-title":"The effects of extracellular pH on immune function","volume":"69","author":"Lardner","year":"2001","journal-title":"J leukocyte Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1743","article-title":"Neutralization of tumor acidity improves antitumor responses to immunotherapy","volume":"76","author":"Pilon-Thomas","year":"2016","journal-title":"Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nature13490","article-title":"Functional polarization of tumour-associated macrophages by tumour-derived lactic acid","volume":"513","author":"Colegio","year":"2014","journal-title":"Nature."},{"key":"B14","first-page":"15","article-title":"Pathophysiology of bone cancer pain","volume":"3","author":"Sabino","year":"2005","journal-title":"J supportive Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1007\/s00774-006-0734-8","article-title":"Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization","volume":"25","author":"Nagae","year":"2007","journal-title":"J Bone mineral Metab"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3815-04.2005","article-title":"Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain","volume":"25","author":"Ghilardi","year":"2005","journal-title":"J Neurosci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/39807","article-title":"The capsaicin receptor: a heat-activated ion channel in the pain pathway","volume":"389","author":"Caterina","year":"1997","journal-title":"Nature."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.46.28819","article-title":"The acid-sensitive ionic channel subunit ASIC and the mammalian degenerin MDEG form a heteromultimeric h+-gated na+ channel with novel properties","volume":"272","author":"Bassilana","year":"1997","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","first-page":"S209","DOI":"10.1016\/j.bone.2009.03.035","article-title":"Involvement of osteoclast-released protons in bone cancer pain","volume":"44","author":"Yoneda","year":"2009","journal-title":"Bone."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2006.04.033","article-title":"Osteoclasts play a part in pain due to the inflammation adjacent to bone","volume":"39","author":"Nagae","year":"2006","journal-title":"Bone."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5484.1504","article-title":"Bone resorption by osteoclasts","volume":"289","author":"Teitelbaum","year":"2000","journal-title":"Science."},{"key":"B22","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.neo.2014.04.005","article-title":"Mechanisms of buffer therapy resistance","volume":"16","author":"Bailey","year":"2014","journal-title":"Neoplasia."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2796","article-title":"Acidity generated by the tumor microenvironment drives local invasion","volume":"73","author":"Estrella","year":"2013","journal-title":"Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-011-9415-7","article-title":"Reduction of metastasis using a non-volatile buffer","volume":"28","author":"Ibrahim Hashim","year":"2011","journal-title":"Clin Exp metastasis."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5575","article-title":"Bicarbonate increases tumor pH and inhibits spontaneous metastases","volume":"69","author":"Robey","year":"2009","journal-title":"Cancer Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1032","article-title":"Tris-base buffer: A promising new inhibitor for cancer progression and metastasis","volume":"6","author":"Ibrahim-Hashim","year":"2017","journal-title":"Cancer Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"6","DOI":"10.4172\/2155-9600.S2-006","article-title":"Buffer therapy for cancer","volume":"2","author":"Ribeiro","year":"2012","journal-title":"J Nutr Food Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2012.03.113","article-title":"Systemic buffers inhibit carcinogenesis in TRAMP mice","volume":"188","author":"Ibrahim-Hashim","year":"2012","journal-title":"J urology."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2844","article-title":"Defining cancer subpopulations by adaptive strategies rather than molecular properties provides novel insights into intratumoral evolution","volume":"77","author":"Ibrahim-Hashim","year":"2017","journal-title":"Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1186\/1479-5876-11-268","article-title":"Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients\u2019 bed","volume":"11","author":"Ferrari","year":"2013","journal-title":"J Trans Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s13046-015-0194-x","article-title":"Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer","volume":"34","author":"Wang","year":"2015","journal-title":"J Exp Clin Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2016.08.126","article-title":"High-doses of proton pump inhibitors in refractory gastro-intestinal cancer: A case series and the state of art","volume":"48","author":"Falcone","year":"2016","journal-title":"Dig Liver Dis"},{"key":"B33","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1186\/1479-5876-9-221","article-title":"Lansoprazole as a rescue agent in chemoresistant tumors: a phase I\/II study in companion animals with spontaneously occurring tumors","volume":"9","author":"Spugnini","year":"2011","journal-title":"J Trans Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/s12967-014-0225-y","article-title":"High dose lansoprazole combined with metronomic chemotherapy: a phase I\/II study in companion animals with spontaneously occurring tumors","volume":"12","author":"Spugnini","year":"2014","journal-title":"J Trans Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1186\/s12967-015-0735-2","article-title":"Evidence-based support for the use of proton pump inhibitors in cancer therapy","volume":"13","author":"Fais","year":"2015","journal-title":"J Trans Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4095","article-title":"Proton pump inhibitors induce apoptosis of human b-cell tumors through a caspase-independent mechanism involving reactive oxygen species","volume":"67","author":"De Milito","year":"2007","journal-title":"Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25009","article-title":"pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity","volume":"127","author":"De Milito","year":"2010","journal-title":"Int J cancer."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.04.015","article-title":"Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma","volume":"376","author":"Canitano","year":"2016","journal-title":"Cancer letters."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-14-0002","article-title":"Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma","volume":"7","author":"Papagerakis","year":"2014","journal-title":"Cancer Prev Res (Phila)."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1329","article-title":"Negative association of proton pump inhibitors with subsequent development of breast cancer: A nationwide population-based study","volume":"59","author":"Chen","year":"2019","journal-title":"J Clin Pharmacol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/tbj.13519","article-title":"Proton pump inhibitors reduce breast cancer risk in gastric ulcer patients: A population-based cohort study","volume":"26","author":"Ding","year":"2020","journal-title":"Breast J"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-017-3426-2","article-title":"Repositioning of proton pump inhibitors in cancer therapy","volume":"80","author":"Lu","year":"2017","journal-title":"Cancer Chemother Pharmacol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00911","article-title":"Drug repositioning of proton pump inhibitors for enhanced efficacy and safety of cancer chemotherapy","volume":"8","author":"Ikemura","year":"2017","journal-title":"Front Pharmacol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1080\/13543776.2020.1704733","article-title":"Drug repurposing for anticancer therapies. a lesson from proton pump inhibitors","volume":"30","author":"Spugnini","year":"2020","journal-title":"Expert Opin Ther Patents."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e0159763","DOI":"10.1371\/journal.pone.0159763","article-title":"Effect of modified alkaline supplementation on syngenic melanoma growth in CB57\/BL mice","volume":"11","author":"Azzarito","year":"2016","journal-title":"PloS One"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2016.1252760","article-title":"Systemic alkalinisation delays prostate cancer cell progression in TRAMP mice","volume":"32","author":"Astigiano","year":"2017","journal-title":"J Enzyme inhibition medicinal Chem"},{"key":"B47","doi-asserted-by":"publisher","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J Basic Clin Pharm"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1542\/peds.53.3.414","article-title":"Sodium bicarbonate prophylaxis of sickle cell crisis","volume":"53","author":"Mann","year":"1974","journal-title":"Pediatrics."},{"key":"B49","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0736-4679(98)00123-1","article-title":"Severe metabolic alkalosis due to baking soda ingestion: case reports of two patients with unsuspected antacid overdose","volume":"17","author":"Fitzgibbons","year":"1999","journal-title":"J Emerg Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1124\/mi.10.3.7","article-title":"Mechanism of cancer pain","volume":"10","author":"Schmidt","year":"2010","journal-title":"Mol Interv."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.6.2403","article-title":"Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial","volume":"15","author":"Burris","year":"1997","journal-title":"J Clin Oncol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.07.9525","article-title":"Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of Canada clinical trials group","volume":"25","author":"Moore","year":"2007","journal-title":"J Clin Oncol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4172\/2155-9600.1000685","article-title":"Buffer therapy\u2013>Buffer diet","volume":"8","author":"Pilot","year":"2018","journal-title":"K Nutr Food Sci"},{"key":"B54","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/1743-7075-9-72","article-title":"Examining the relationship between diet-induced acidosis and cancer","volume":"9","author":"Robey","year":"2012","journal-title":"Nutr Metab (Lond)."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/68.3.576","article-title":"Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents","volume":"68","author":"Frassetto","year":"1998","journal-title":"Am J Clin Nutr"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1972.43","article-title":"Symposium on acid-base homeostasis. the generation and maintenance of metabolic alkalosis","volume":"1","author":"Seldin","year":"1972","journal-title":"Kidney Int"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2394","article-title":"The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion","volume":"69","author":"Silva","year":"2009","journal-title":"Cancer Res"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.981718\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:39:53Z","timestamp":1668386393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.981718\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,14]]},"references-count":57,"alternative-id":["10.3389\/fonc.2022.981718"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.981718","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.742433214.793598484","asserted-by":"object"}]},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,14]]},"article-number":"981718"}}