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Review
, 16 (3-4), 144-53

A New View of Carcinogenesis and an Alternative Approach to Cancer Therapy

Affiliations
Review

A New View of Carcinogenesis and an Alternative Approach to Cancer Therapy

Miguel López-Lázaro. Mol Med.

Abstract

During the last few decades, cancer research has focused on the idea that cancer is caused by genetic alterations and that this disease can be treated by reversing or targeting these alterations. The small variations in cancer mortality observed during the previous 30 years indicate, however, that the clinical applications of this approach have been very limited so far. The development of future gene-based therapies that may have a major impact on cancer mortality may be compromised by the high number and variability of genetic alterations recently found in human tumors. This article reviews evidence that tumor cells, in addition to acquiring a complex array of genetic changes, develop an alteration in the metabolism of oxygen. Although both changes play an essential role in carcinogenesis, the altered oxygen metabolism of cancer cells is not subject to the high genetic variability of tumors and may therefore be a more reliable target for cancer therapy. The utility of this novel approach for the development of therapies that selectively target tumor cells is discussed.

Figures

Figure 1
Figure 1
Cancer development requires both the acquisition of DNA alterations and a change in the metabolism of oxygen (dysoxic metabolism). (A) The uncontrolled cell proliferation that characterizes cancer requires signals for cell proliferation and the synthesis of new macromolecules (for example, nucleic acids, lipids, proteins). Glycolysis provides building blocks (for example, glucose 6-phosphate, dihydroxyacetone phosphate, 3-phosphoglycerate, phosphoenolpyruvate, pyruvate) that participate in the synthesis of these macromolecules. The presence of O2 can inhibit glycolysis (Pasteur effect) and, therefore, the biosynthesis of new macromolecules required for the uncontrolled cell proliferation that characterizes cancer. (B) A change in the metabolism of O2 (dysoxic metabolism) would allow the activation of glycolysis in the presence of O2 and, therefore, cell proliferation and cancer development.
Figure 2
Figure 2
Models of carcinogenesis. In addition to the acquisition a complex array of DNA alterations proposed in the accepted model of carcinogenesis (A), the model discussed in this review (B) proposes that cancer develops an alteration in the metabolism of oxygen. Although both changes must interact for the development of cancer, the altered oxygen metabolism of tumor cells is not subject to the high genetic complexity and variability of tumors and may therefore be a more reliable target for cancer therapy.
Figure 3
Figure 3
Carcinogenic agents can induce DNA alterations and an alteration in the metabolism of oxygen. This figure represents an example of how a carcinogenic agent can induce both DNA alterations and a dysoxic metabolism via P450. See text for references and further details.
Figure 4
Figure 4
Utility of the altered oxygen metabolism of cancer cells to selectively kill them. Cancer cells and normal cells metabolize oxygen differently. Because the basal levels of H2O2 are higher in cancer cells than in normal cells, a specific increase in the concentrations of H2O2 may lead to cytotoxic concentrations in cancer cells but not in normal cells. In addition, because the activation of glycolysis in cancer cells is essential to prevent cell death induced by ATP depletion and H2O2 accumulation, the attenuation of glycolysis in cancer cells can induce their death. Normal cells would be less affected by this strategy, because they do not need to have increased glycolytic rates to ensure their survival. See text for further details. Dotted lines indicate that the pathway or process is repressed. Bolded lines indicate that the process is activated or that the levels of the molecule are increased.
Figure 5
Figure 5
Key role of glycolysis in the detoxification of H2O2. Increased glucose metabolism helps detoxify H2O2 by increasing the levels of the H2O2 scavenger pyruvate and by regenerating NADPH. Glutathione reductase (GR) and thioredoxin reductase (TrxR) need NADPH to regenerate glutathione (GSH) and thioredoxin [Trx(SH)2], which are used by glutathione peroxidase (GPx) and thioredoxin peroxidase (TPx) to detoxify H2O2. Thiol (SH)-reactive agents can react with the SH groups of GSH and Trx(SH)2 and induce a prooxidant effect by disrupting the GR/GPx and TrxR/TPx antioxidant systems.

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