Manipulating pH in Cancer Treatment: Alkalizing Drugs and Alkaline Diet

Longhi Alessandra
Submission: March 14, 2017; Published: April 20, 2017
*Corresponding author: Longhi Alessandra MD, Ist Ortopedico Rizzoli, Bologna, Italy

Abstract

Neoplastic cells have inverted pHi/pHe gradient compared to a normal cell and a higher acid extracellular micro environment is a feature of cancer tissue. It is well known the role of acidity in cancer growth and metastatization. Many research studies have been undertaken and even more are ongoing to study the possibility to interfere with cancer cell growth modifying the intracellular or extracellular pH with different mechanisms. Different drugs that inhibit H+ intracellular extrusion via membrane proton pumps inhibitors or mitochondrial poisons that increase intracellular acidity have been tested in cancer cells in preclinical studies, human studies are very few but promising.Some literature underlines the value of alkaline diet as co-adjuvant for cancer treatment, but human randomized studies on the effectiveness of alkaline diet or alkaline water are lacking. We have to understand if it is possible and how to translate the laboratory results in clinical results in cancer patients

Introduction

The rationale for alkalizing pH in cancer microenvironment The increased acidity of tumor tissue is due to:A.  

Increased production al lactate due to the increased anaerobic glycolytic pathway used by cancer cells (Warburg effect).B.  Hypoxia due to low O2 concentration due to hypo perfusion [1].

Neoplastic cells have an intracellular pH(pHi)/extracellular pH(pHe) gradient inverted compared to normal cells. Normal cells usually have a slightly acid pHi (6.99-7.05) and a more alkaline pHe (7.3-7.4). In neoplastic cells the pHi is more alkaline (7.1-7.7) and the pHe is more acid (6.2-6.9) [2]. The development and maintenance of this reversed pH gradient are directly owing to the proton (H+) secretory ability of the tumor cells. This proton secretion depends on the buffering capacity of the cell and it is driven by a series of transporters and enzymes that helps to keep the pHi in alkaline range and expel the excess of acidity in the extracellular environment.

The acidity of extracellular environment is essential for cancer cell proliferation, for invasion and metastatization and it also plays a role in chemotherapy and radiotherapy resistance [3,4] Besides, acidity of extracellular environment has a role in inhibition of Natural Killer and T cytotoxic lymphocytes [5,6]. In order to survive in a low pH-environment tumor cells develop regulatory mechanisms which keep their intracellular pH stable [7].

Several preclinical studies have shown how an inhibition of these regulatory systems (pumps transporters) can reverse the pHe acidity in cancer and increase the pHi acidity that cause apoptosis. The inhibition of these pump transporters can be obtained with commonly used drugs such as PPInhibitors,

Sodium Bicarbonate, amiloride, acetazolamide that can reverse the pH gradient increasing the intracellular H concentration and subsequent acidity as shown in preclinical studies [8,9].  The most important systems to keep intracellular /extracellular H ion gradient stable are:A.  Vacuolar ATPase proton pump.B.  The sodium–proton exchanger family (NHE),C.  The bicarbonate transporter family (BCT)D.  The mono carboxylate transporter family (MCT)E.  Carbonic anidrase 9 (CAIX)F.  Voltage gated Sodium channel (VGSC) (Figure 1)

Introduction

The rationale for alkalizing pH in cancer microenvironment

The increased acidity of tumor tissue is due to: A.  Increased production al lactate due to the increased anaerobic glycolytic pathway used by cancer cells (Warburg effect).B.  Hypoxia due to low O2 concentration due to hypo perfusion [1].Neoplastic cells have an intracellular pH(pHi)/extracellular pH(pHe) gradient inverted compared to normal cells. Normal cells usually have a slightly acid pHi (6.99-7.05) and a more alkaline pHe (7.3-7.4). In neoplastic cells the pHi is more alkaline (7.1-7.7) and the pHe is more acid (6.2-6.9) [2]. The development and maintenance of this reversed pH gradient are directly owing to the proton (H+) secretory ability of the tumor cells. This proton secretion depends on the buffering capacity of the cell and it is driven by a series of transporters and enzymes that helps to keep the pHi in alkaline range and expel the excess of acidity in the extracellular environment.The acidity of extracellular environment is essential for cancer cell proliferation, for invasion and metastatization and it also plays a role in chemotherapy and radiotherapy resistance [3,4] 

Besides, acidity of extracellular environment has a role in inhibition of Natural Killer and T cytotoxic lymphocytes [5,6]. 
In order to survive in a low pH-environment tumor cells develop regulatory mechanisms which keep their intracellular pH stable [7].

Several preclinical studies have shown how an inhibition of these regulatory systems (pumps transporters) can reverse the pHe acidity in cancer and increase the pHi acidity that cause apoptosis. The inhibition of these pump transporters can be obtained with commonly used drugs such as PPInhibitors, Sodium Bicarbonate, amiloride, acetazolamide that can reverse the pH gradient increasing the intracellular H concentration and subsequent acidity as shown in preclinical studies [8,9].  The most important systems to keep intracellular /extracellular H ion gradient stable are:A.  Vacuolar ATPase proton pump.B.  The sodium–proton exchanger family (NHE),C.  The bicarbonate transporter family (BCT)D.  The mono carboxylate transporter family (MCT)E.  Carbonic anidrase 9 (CAIX)F.  Voltage gated Sodium channel (VGSC) (Figure 1)