Triple-edged therapy targeting intracellular alkalosis and extracellular acidosis in cancer

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

“…From the point of view of metabolism, the therapeutic strategy to be recommended in human cancer is mainly directed to achieve an apoptosis-inducing IA of malignant cells while sparing normal cells. This IA must achieve a pHi low enough to induce a chain reaction that leads to selective apoptosis [13,21,43,101,102]. During this apoptotic process the endonuclease DNAase I becomes another fundamental mediating factor [103].…”

“…Similarly, a low pHi-induced apoptosis is also mediated through other different mechanisms [21], while the Bcl-2 anti-apoptotic protein seems unable to inhibit it [104]. This is why IA is the main and fundamental weapon of the pH-centered anticancer treatment [102]. IA can be achieved through inhibition of NHE1 and/or H + -ATPase and/or CAs IX and XII and/or successful chemotherapy.…”

“…Their extracellular acidity (EA) is a basic requirement for their highly invasive capacity [127]. Importantly, a two-edged or even triple-edged treatment that addresses simultaneously glucose availability and the pH alterations found in brain tumors may represent an important step forward towards decreasing the migration/invasion process of GBM [102].…”

Curing cancer? Further along the new pH-centric road and paradigm

“…The pH dynamics of cancer cells, and specifically, the pH- or proton gradient reversal, now appears as a specific abnormality and even the most differential metabolic trait of all and each type of cancer. Therefore, this new cancer paradigm should and hopefully soon would be successfully exploited in any approach to selective cancer therapeutics [ 3 , 7 ].…”

The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers

“…As a consequence of the metabolic shift in cancer, the degradation of glucose in malignant cells by aerobic glycolysis will lead to the production of large amounts of lactic acid and a concomitant increase in proton (H + ) concentration inside the cancer cells. For this reason, in order to avoid the apoptotic response that would induce this acid stress, malignant cells use several mechanisms to extrude this excess of H + from the cytoplasm by plasma membrane-bound proton transporters and proton pumps that are upregulated in tumors, provoking a decrease of the tumor extracellular pH (pH e ) and a concomitant increase of the intracellular pH (pH i ) 11 ( Fig. 1 ).…”