Tissue Redox Activity as a Hallmark of Carcinogenesis: From Early to Terminal Stages of Cancer

Abstract

Purpose: The study aimed to clarify the dynamics of tissue redox activity (TRA) in cancer progression and assess the importance of this parameter for therapeutic strategies.Experimental Design: The experiments were carried out on brain tissues of neuroblastoma-bearing, glioma-bearing, and healthy mice. TRA was visualized in vivo by nitroxide-enhanced MRI on anesthetized animals or in vitro by electron paramagnetic resonance spectroscopy on isolated tissue specimens. Two biochemical parameters were analyzed in parallel: tissue total antioxidant capacity (TTAC) and plasma levels of matrix metalloproteinases (MMP).Results: In the early stage of cancer, the brain tissues were characterized by a shorter-lived MRI signal than that from healthy brains (indicating a higher reducing activity for the nitroxide radical), which was accompanied by an enhancement of TTAC and MMP9 plasma levels. In the terminal stage of cancer, tissues in both hemispheres were characterized by a longer-lived MRI signal than in healthy brains (indicating a high-oxidative activity) that was accompanied by a decrease in TTAC and an increase in the MMP2/MMP9 plasma levels. Cancer progression also affected the redox potential of tissues distant from the primary tumor locus (liver and lung). Their oxidative status increased in both stages of cancer.Conclusions: The study shows that tissue redox balance is very sensitive to the progression of cancer and can be used as a diagnostic marker of carcinogenesis. The study also suggests that the noncancerous tissues of a cancer-bearing organism are susceptible to oxidative damage and should be considered a therapeutic target.

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

“…Our data imply that, while the reactions of MnP are likely identical, the magnitude and the end results of such reactions may be profoundly different in normal versus cancer cells, as much as in one versus another cancer cell type. Based on our present understanding, the resulting effects of electron shuttling by MnPs may be prooxidative rather than antioxidative, and particularly so in cancer cells that are already under the conditions of increased oxidative stress (16). The modes of action, other than antioxidative, have also been speculated for Mn salens (229) and polyphenols, and discussed by Forman et al for natural compunds commonly viewed as antioxidants (16,107,108,260).…”

“…Thus, potent SOD mimics are potent peroxynitrite scavengers (Eqs. [15] and [16] P production, can only bear antioxidative character if the cell has either sufficient peroxide-removing enzymes or reductants to eliminate strong oxidants (high valent metal), respectively. If not, as is often the case with oxidative stress injuries and in a particular cancer, the pro-oxidative action may prevail.…”

Mitochondrial Dysfunction and Redox Imbalance as a Diagnostic Marker of “Free Radical Diseases”

“…For example, nitroxides as mito-TEMPO and mito-carboxy-PROXYL are mitochondria-targeted derivatives of TEMPOL and carboxy-PROXYL, which currently are widely used as redox-sensors for detection of abnormal superoxide generation in living cells and tissues (2,28,37,(88)(89)(90)(91).…”

“…In vitro studies have demonstrated that various reducers or oxidizers may convert the contrast form of nitroxide radical to non-contrast hydroxylamine, which depends on physiological conditions (2,28,91,93). Figure 5 shows the transformations between the oxidation radical state of nitroxide, hydroxylamine, and oxoammonium states.…”

“…Thus, the ratio between radical and hydroxylamine forms directly depends on the redox status of the cells and tissues. Since only the radical form is characterized by EPR/MRI contrast, this could be used as a quantitative marker for the as-sessment of the redox status in biological objects in vitro and in vivo (91). Many excellent review articles have described this possibility (92,(95)(96)(97)(98).…”