Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies

Abstract

The treatment of cancer has been slowly but steadily progressing during the last fifty years. Some tumors with a high mortality in the past are curable nowadays. However, there is one striking exception: glioblastoma multiforme. No real breakthrough has been hitherto achieved with this tumor with ominous prognosis and very short survival. Glioblastomas, being highly glycolytic malignancies are strongly pH-dependent and driven by the sodium hydrogen exchanger 1 (NHE1) and other proton (H+) transporters. Therefore, this is one of those pathologies where the lessons recently learnt from the new pH-centered anticancer paradigm may soon bring a promising change to treatment. This contribution will discuss how the pH-centric molecular, biochemical and metabolic perspective may introduce some urgently needed and integral novel treatments. Such a prospective therapeutic approach for malignant brain tumors is developed here, either to be used alone or in combination with more standard therapies.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…NHE1 levels are higher in BC tissue than in normal breast tissue, and also in resistant BC cells than in sensitive cells, in a similar fashion to other PTs [ 4 , 10 , 51 , 55 , 56 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Apart from NHE1 overexpression, carbonic anhydrases also have an important role in the pathogenesis of BC, like V-ATPase proton pumps, the Na + –HCO 3 − cotransporter (SLC4A7,NBCn1, MCTs, hypoxia and hypoxia-inducing factor 1 (HIF-1) [ 75 ].…”

“…A similar protumoral effect has certain oncogenes, gene mutations and products like BRCA1 and BRCA2 , apart from a dysfunctional p53 [ 76 ] and certain chemicals known to play a role in carcinogenesis [ 77 , 78 ]. These myriad factors belong to an already large list of mediating causes of cancer and BC previously reported [ 10 , 11 ]. This large amount of data demonstrates that many different etiological factors of different natures and origins all act through pHi/pHe dysregulation in the same direction, exerting a carcinogenic effect on BC pathogenesis.…”

“…The new pH-based strategy allows us to interfere with all of cancer’s metabolic hallmarks, from prevention to the treatment of advanced disease. From this perspective, our group has recently published two conceptual publications, one on the pH-related etiopathogenesis and treatment of brain tumors [ 10 ], and a second one on breast cancer [ 11 ].…”

“…For him, those mysteries were still hiding in the future and were very far removed from the way we understand them nowadays. They were made possible only decades later, thanks to our increasing knowledge of the role of proton extruders/and/or membrane cell-bound H + transporters and pumps (PTs and PPs) in elevating pHi and decreasing pHe (so increasing CPR) in all cancer cells and tissues [ 4 , 10 , 28 ]. A few decades later, Proton emission tomography (PET) technology would bring a revival of interest in Warburg’s genial work and theories: serendipity at work.…”

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

“…The pH dysregulation observed in cancer cells helps to drive tumor processes, which are highly sensitive to even minimum pHi variations: these are cancer initiation, progression, adaptation, proliferation, migration, and the programming and reprogramming of tumor cell metabolism [14,[123][124][125][126][127]. Furthermore, many effects on biologic processes of a cell are generated as a result of pH-sensitive functions such as the regulation of protein expression, the affinity of proteins to bind with a ligand as well as the activity of ion channels/enzymes [124,128].…”