Integrative Cancer Therapies Addressing Tumoral Metabolic Pathways

Many (bio)chemical reactions take place as electron or proton transfer reactions and are characterized by redox potential or pH value. Biological systems closely control these parameters and deviations from the norm have been known for decades under the terms oxidosis/redosis or acidosis/alkalosis. In this regard, proliferating cancer cells exhibit a permanent redosis with an increased accumulation of reduced glutathione, NADH, NADPH, cysteine and glucose, respectively. In accordance with the existing redosis, a permanent intracellular alkalinization of the tumor cells (pHi 7.12 – 7.65) compared to normal cells (pHi 6.99-7.20) is documented.

The permanent intracellular alkalinization of proliferating cancer cells is largely due to an activation of the Na⁺/ H⁺ antiporter system NHE1, the V-ATPase proton pump and the MCT lactate transporter, which ensure an uninterrupted release of protons (H⁺) and lactate into the extracellular space. The Zn-dependent carbonic anhydrases (CA2, CA9, CA12) also contribute to a markedly acidic environment in the tumor tissue (pHe 6.2 – 6.9) compared to normal tissue (pHe 7.3 – 7.4), a fact that clearly promotes both tumor growth and metastasis, while also blocking the activity of immunocompetent cells.

The above-mentioned intracellular alkalinization of the tumor cells also leads to a strong activation of the HIF1 transcriptional factor and aerobic glycolysis, which was already described in the 1930s as the Warburg effect. On the other hand, the overexpression of glucose transporters on the surface of tumor cells ensures a sensible increase in the uptake of glucose, which then serves as the main source of energy for tumor metabolism.

The hijacked metabolism uses the most common amino acid in blood and muscle tissue, glutamine, to derive from it the nitrogen and carbon atoms to be used as building blocks for the synthesis of purine and pyrimidine bases, as well as amino acids, especially Ala, Ser, Asn, Orn. For this purpose, the body’s reserves of glutamine are depleted in a process known as glutaminolysis, leading to rapid muscle breakdown and cachexia in cancer patients.

It is important to note that other amino acids such as Asp, Arg, Leu, Ile and cystine/cysteine can also increase protein and nucleotide synthesis via mTOR activation and thus promote the proliferation of cancer cells. (1) Recent research results indicate that “amino acids and not glucose contribute most of the cell mass in proliferating cancer cells”.

Finally, glucose or glutamate are used also as building block sources for the synthesis of saturated fatty acids from citrate, in reactions catalyzed by ATP-citrate lyase, acetyl-CoA carboxylase and fatty acid synthase (FAS or FASN). This is why a strong expression of FAS in various types of cancer correlates with a poor prognosis.

In view of the high genetic variability of cancer cells, the above-mentioned molecular biological characteristics are of particular importance in the diagnosis and treatment of therapy-resistant neoplastic diseases. Such new therapeutic approaches with a significant anti-proliferative and pro-apoptotic effect include 1) the elimination of intracellular redosis with the aid of pro-oxidative approaches, 2) the use of alkaline solutions to buffer extracellular acidosis, 3) the use of high doses of vitamin C i.v. and polyphenols with the formation of higher ROS concentrations in situ, 4) the use of proton pump inhibitors, inhibitors of the Na⁺/H⁺ antiporter system and carbonic anhydrases, 5) the selection of an appropriate diet with a low glycemic index and ketogenic or pro-oxidative properties, 6) the inhibition of aerobic glycolysis, glutaminolysis and fatty acid synthesis with the aid of specific inhibitors.