Targeting the pH Paradigm at the Bedside: A Practical Approach

Abstract

The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the “cancer problem”? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article’s goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.

Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach

“…Table 1 summarizes these data with the appropriate references. However, some reviews have emphasized the importance of acidity in tumors, proposing some approaches to counteract it [ 26 , 27 , 49 ]. Many of the purposes behind newly treated microenvironmental acidity come from the new paradigm of using the off-targeting of old drugs [ 5 ], but some interesting and novel approaches to finding new anti-cancer drugs in the panel of available drugs have recently been proposed [ 50 ], thus opening a promising future for this issue.…”

Metabolic Classification and Intervention Opportunities for Tumor Energy Dysfunction

“…Nevertheless, this is an emerging field with heterogeneous results, which urges caution [ 114 ]. Several studies have been conducted on the regulation of membrane transporters, electrolyte exchangers, enzymes, water trafficking, modifications of membrane structure, transcription factor deviation, metabolic changes, and many other effects of lactate accumulation due to tumor metabolic alteration [ 115 ]. Further studies in this field will enhance our understanding of common pathophysiological mechanisms shared by different diseases, such as metabolic disorders and malignant tumors [ 116 ].…”

Effect of Exogenous pH on Cell Growth of Breast Cancer Cells

“…Lactate secretion by cancer cells, in turn, leads to extracellular acidification [ 14 , 15 ]. Moreover, cancer cells increase the expression and the activation of transporters and pumps such as the Na + /H + exchanger (NHE-1), the H + -lactate co-transporter, and the proton pump (H + -ATPase), which increases the secretion of H + into the extracellular environment of the cells, further contributing to extracellular acidification [ 16 , 17 ]. Therefore, cancer cells have a reversed pH gradient with a slightly elevated intracellular pH and a slightly lowered extracellular pH [ 18 , 19 ].…”