Systems Biology (Methods in Molecular Biology)

bicarbonate, the exchanger NA+/H+(NHE), Which is a prominent

mediator of the export of protons, as is the H+-ATPasa vacuolar

(V-ATPasa), Which hydrolyzes ATP and pumps protons [126].

A cancer-specific intracellular alkalosis represents a common

final pathway in cell transformation and an antiapoptotic defensive

mechanism in cancer cells. In terms of mechanisms, it is known that

decreasing intracellular pH induces a cell death program, either via

apoptosis or necrosis, while the elevation of cellular pH by different

methods protects cancer cells by preventing them from entering the

apoptotic cascade [127].

Environmental acidification, mediated by overexpression of

either NHE and/or other PTs, is known to play a role in hindering

DNA repair, increasing mutagenesis, and driving genomic instabil-

ity in cancer [127].

Cytosolic acidification in cancer cells during apoptosis was accom-

panied by the activation of OXPHOS. Some recent reports have

shown that the intracellular pH plays a key role in determining the

way cancer cells obtain energy. Thus, an alkaline pHidrives aerobic

glycolysis and an acidic pHidrives oxidative phosphorylation [125].

As an alternative or common strategy with the correction of

pHeacid in tumors, a large number of investigations have explored

the inhibition of membrane ion pumps that maintain the pH alka-

line in the intracellular medium, by exporting protons or importing

bicarbonate [128].

Inhibition of proton pumps decreases the value of pHiand this

tends to increase the value of pHe. The effect in pHeis sustained

Fig. 9Entropy production rate [J/K min]10^3 for reaction ATPase as a function of intracellular pHi, for
glycolysis network model AS-30D and HeLa cells

154 Sheyla Montero et al.