Cancer: fundamentals behind pH targeting and the double-edged approach
Tomas Koltai Obra Social del Personal de la Industria Alimenticia, Filial Capital Federal, Republic of Argentina Abstract: The highly regulated pH of cells and the less-regulated pH of the surrounding extracellular matrix (ECM) is the result of a delicate balance between metabolic processes and pr...
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doaj-69e451454d0d4db9acb618f4929863122020-11-24T23:01:04ZengDove Medical PressOncoTargets and Therapy1178-69302016-10-01Volume 96343636029479Cancer: fundamentals behind pH targeting and the double-edged approachKoltai TTomas Koltai Obra Social del Personal de la Industria Alimenticia, Filial Capital Federal, Republic of Argentina Abstract: The highly regulated pH of cells and the less-regulated pH of the surrounding extracellular matrix (ECM) is the result of a delicate balance between metabolic processes and proton production, proton transportation, chemical buffering, and vascular removal of waste products. Malignant cells show a pronounced increase in metabolic processes where the 10- to 15-fold rise in glucose consumption is only the tip of the iceberg. Aerobic glycolysis (Warburg effect) is one of the hallmarks of cancer metabolism that implies excessive production of protons, which if stayed inside the cells would result in fatal intracellular acidosis (maintaining a strict acid–base balance is essential for the survival of eukaryotic cells). Malignant cells solve this problem by increasing mechanisms of proton transportation which expel the excess acidity. This allows cancer cells to keep a normal intracellular pH, or even overshooting this mechanism permits a slightly alkaline intracellular tendency. The proton excess expelled from malignant cells accumulates in the ECM, where chronic hypoxia and relative lack of enough blood vessels impede adequate proton clearance, thus creating an acidic microenvironment. This microenvironment is quite heterogeneous due to the tumor’s metabolic heterogeneity and variable degrees of hypoxia inside the tumor mass. The acidic environment (plus other necessary cellular modifications) stimulates migration and invasion and finally intravasation of malignant cells which eventually may result in metastasis. Targeting tumor pH may go in two directions: 1) increasing extracellular pH which should result in less migration, invasion, and metastasis; and 2) decreasing intracellular pH which may result in acidic stress and apoptosis. Both objectives seem achievable at the present state of the art with repurposed drugs. This hypothesis analyzes the altered pH of tumors and its implications for progression and metastasis and also possible repurposed drug combinations targeting this vulnerable side of cancer development. It also analyzes the double-edged approach, which consists in pharmacologically increasing intracellular proton production and simultaneously decreasing proton extrusion creating intracellular acidity, acid stress, and eventual apoptosis. Keywords: metabolic processes, malignant cells, acid, apoptosis, Warburg effecthttps://www.dovepress.com/cancer-fundamentals-behind-ph-targeting-and-the-double-edged-approach-peer-reviewed-article-OTTpHaciditycancerNHE1VGSCCarbonic anhydrasemetforminamilorideacetazolamide. |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Koltai T |
spellingShingle |
Koltai T Cancer: fundamentals behind pH targeting and the double-edged approach OncoTargets and Therapy pH acidity cancer NHE1 VGSC Carbonic anhydrase metformin amiloride acetazolamide. |
author_facet |
Koltai T |
author_sort |
Koltai T |
title |
Cancer: fundamentals behind pH targeting and the double-edged approach |
title_short |
Cancer: fundamentals behind pH targeting and the double-edged approach |
title_full |
Cancer: fundamentals behind pH targeting and the double-edged approach |
title_fullStr |
Cancer: fundamentals behind pH targeting and the double-edged approach |
title_full_unstemmed |
Cancer: fundamentals behind pH targeting and the double-edged approach |
title_sort |
cancer: fundamentals behind ph targeting and the double-edged approach |
publisher |
Dove Medical Press |
series |
OncoTargets and Therapy |
issn |
1178-6930 |
publishDate |
2016-10-01 |
description |
Tomas Koltai Obra Social del Personal de la Industria Alimenticia, Filial Capital Federal, Republic of Argentina Abstract: The highly regulated pH of cells and the less-regulated pH of the surrounding extracellular matrix (ECM) is the result of a delicate balance between metabolic processes and proton production, proton transportation, chemical buffering, and vascular removal of waste products. Malignant cells show a pronounced increase in metabolic processes where the 10- to 15-fold rise in glucose consumption is only the tip of the iceberg. Aerobic glycolysis (Warburg effect) is one of the hallmarks of cancer metabolism that implies excessive production of protons, which if stayed inside the cells would result in fatal intracellular acidosis (maintaining a strict acid–base balance is essential for the survival of eukaryotic cells). Malignant cells solve this problem by increasing mechanisms of proton transportation which expel the excess acidity. This allows cancer cells to keep a normal intracellular pH, or even overshooting this mechanism permits a slightly alkaline intracellular tendency. The proton excess expelled from malignant cells accumulates in the ECM, where chronic hypoxia and relative lack of enough blood vessels impede adequate proton clearance, thus creating an acidic microenvironment. This microenvironment is quite heterogeneous due to the tumor’s metabolic heterogeneity and variable degrees of hypoxia inside the tumor mass. The acidic environment (plus other necessary cellular modifications) stimulates migration and invasion and finally intravasation of malignant cells which eventually may result in metastasis. Targeting tumor pH may go in two directions: 1) increasing extracellular pH which should result in less migration, invasion, and metastasis; and 2) decreasing intracellular pH which may result in acidic stress and apoptosis. Both objectives seem achievable at the present state of the art with repurposed drugs. This hypothesis analyzes the altered pH of tumors and its implications for progression and metastasis and also possible repurposed drug combinations targeting this vulnerable side of cancer development. It also analyzes the double-edged approach, which consists in pharmacologically increasing intracellular proton production and simultaneously decreasing proton extrusion creating intracellular acidity, acid stress, and eventual apoptosis. Keywords: metabolic processes, malignant cells, acid, apoptosis, Warburg effect |
topic |
pH acidity cancer NHE1 VGSC Carbonic anhydrase metformin amiloride acetazolamide. |
url |
https://www.dovepress.com/cancer-fundamentals-behind-ph-targeting-and-the-double-edged-approach-peer-reviewed-article-OTT |
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