Use of pH-interfering agents as chemosensitizers: Clinical studies survey

Abstract It has been widely studied that cancer thrives in hypoxic conditions. The importance of tumor metabolism was already discovered in the 1930s by Otto H. Warburg, and the Warburg effect is described by the ability of cancer cells to ferment sugars independently of the oxygen levels. Yet, there is still a lack of understanding of the mechanisms behind the cancer cell adaptation and survival, e.g., by sugar fermentation with lactate production, extracellular acidification, and finally, the survival of tumor cells in a hostile microenvironment. As a result, there has been growing interest in novel pH interfering agents that could increase the antitumoral effect of chemotherapy or even prevent tumorigenesis. It has been proposed that acidic intratumoral environment/low extracellular pH is one of the key features in tumor chemoresistance. This is theorized as due to excessive amounts of H+, which in turn leads to protonation/neutralization of chemotherapeutic agents, leading to failure to reach their intracellular targets. There is a growing body of evidence about the mechanisms in preclinical models, but data from large clinical trials are still limited. In this chapter, we introduce both recent and current studies on pH-interfering agents that have been investigated in clinical trials.