pH gradient reversal: An emerging hallmark of cancers

Several tumors exhibit pH gradient reversal, with acidification of extracellular pH (pHe) and alkalinization of intracellular pH (pHi). The pH gradient reversal is evident even during the preliminary stages of tumorigenesis and is crucial for survival and propagation of tumors, irrespective of their pathology, genetics and origins. Moreover, this hallmark seems to be present ubiquitously in all malignant tumors. Based on these facts, we propose a new emerging hallmark of cancer “pH gradient reversal”. Normalizing pH gradient reversal through inhibition of various proton transporters such as Na⁺-H⁺ exchanger (NHE), Vacuolar-type H⁺-ATPase (V-ATPase), H⁺/K⁺-ATPases and carbonic anhydrases (CAs) has demonstrated substantial therapeutic benefits. Indeed, inhibition of NHE1 is now being regarded as the latest concept in cancer treatment. A recent patent deals with the utilization of cis-Urocanic acid to acidify the pHi and induce apoptosis in tumors. Another patent reports therapeutic benefit by inhibiting Lactate Dehydrogenase - 5 (LDH-5) in various cancers. Several patents have been formulated by designing drugs activated through acidic pHe providing a cancer specific action. The purpose of this review is to analyze the available literature and help design selective therapies that could be a valuable adjunct to the conventional therapies or even replace them.