presumably because the acidification of pHisuppresses the effi-
ciency of glycolysis. Intracellular acidification associated with inhi-
bition of proton pumps can cause a high impact on cancer behavior
regardless of whether it is associated with decrease of the
pHe[129].
In fact, inhibition of proton pumps exerts an antiproliferative
and pro-apoptotic effect on some cancer cell lines. On the other
hand, intracellular acidification has been shown to be related to the
efficacy of death by hyperthermia (42C). Recently, new variants of
tumor therapies that use hyperthermia have been studied and it is
observed that the low value of the pHiis strongly related to the
thermosensitivity [130].
It is an important possibility as future therapy to combine the
use of proton transport inhibitors along with hyperthermia. Also,
the pHiis linked to the apoptotic response to tumor necrosis factor-
related ligand-inducing apoptosis [131].
A key factor in drug resistance is the inverse gradient of
pH. The pHialkaline confers cancer cells resistance to drug cyto-
toxicity and to the external acidic environment. A large number of
studies [132] have shown that resistance to cisplatin and doxorubi-
cin (anticancer drugs) is associated with elevation of pHiin multiple
tumor cell lines (epidermal cancer, prostate cancer, ovarian cancer,
melanomas, lung cancer, and breast cancer [113]).
In this way, we see how the reaction catalyzed by ATPase
represents a potential target of the glycolysis process in the treat-
ment of cancer, not only because it is the most important in the
regulation of the glycolytic route, but also because it exhibits a
greater dependence with the values the pHitakes.4.2 How Much
Damage Can
the Glucose Make
in Cancer?
Due to a combination of high glucose consumption rates by tumor
cells and reduced tumor vascularization, the glucose concentration
in the tumors can be 3–10 times lower than in normal tissues,
according to the stage of its development. Therefore, tumor cells
must develop strategies for their growth and survival in metaboli-
cally unfavorable environments [133].
Since the last years, cancer glycolysis has been a target in
oncology research [134]. The significant increase in glycolysis rate
observed in tumors has been recently verified, yet only a few oncol-
ogists or cancer researchers understand the full scope of Warburg’s
work [84, 134] despite, as we have said above, its great importance.
Altered energy metabolism is proving to be as widespread in cancer
cells as many of the other cancer-associated traits that have been
accepted as hallmarks of cancer [16]. The regulation of metabolism,
relevant to senescence process, would be a key to improve and
identify new anti-cancer therapies in the future.
The complex systems theory and the thermodynamics formal-
ism in the last years have shown to be a theoretical framework asParameters Estimation in Phase-Space Landscape Reconstruction of Cell Fate... 155