Oxidative stress, redox, and the tumor microenvironment

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Abstract

Cellular metabolism is critical for the generation of energy in biological systems; however, as a result of electron transfer reactions, reactive oxygen species (ROS) are generated in aerobic cells. Although low amounts of ROS are easily tolerated by the cell, abnormally high levels of ROS induce oxidative stress. ROS are also produced after exposure to ionizing radiation, selected chemotherapeutic agents, hyperthermia, inhibition of antioxidant enzymes, or depletion of cellular reductants such as NADPH and glutathione. Oxidative stress such as ionizing radiation produces a variety of highly reactive free radicals that damage cells, initiate signal transduction pathways, and alter gene expression. Cells are capable of countering the effects of oxidative stress by virtue of a complex redox buffering system. With respect to the radiation treatment of cancer, components of the cellular redox armamentarium may be targeted to enhance cell killing in the case of tumors and/or protection in the case of normal tissues.

Section snippets

Defining tumor redox status

The redox environment of cells/tissues has been defined as: Redox environmentEi∗(reduced species) where Ei is the half-cell reduction potential for a given redox couple, and the reduced species is the concentration of the reduced species for a particular redox couple.1 There are 3 main intracellular redox couples: (1) NAD(P)H/NAD(P)+, (2) GSH/GSSG, and (3) Trx(SH)2/TrxSS (thioredoxin system). It is important to note that all these redox couples are linked both kinetically and

Tumor redox environment

There are no extensive studies characterizing tumor redox as outlined earlier. The reason for this resides in the complexity of tumor cell biochemistry compared with normal tissues. Not only is there a considerable degree of heterogeneity with respect to varying oxygen levels and different growth states of tumor cells (log v plateau phase), but there is considerable heterogeneity with respect to cellular composition of the tumor. Solid tumors are commonly infiltrated with a variety of host

Modulation of redox status

Numerous preclinical studies have shown that modulating cellular/tissue redox can enhance and/or protect against the cytotoxicity of specific drugs and radiation. Modulation of 3 components of the cellular redox network is briefly highlighted later. The typical approach has been to either deplete or elevate (overexpress) key components of the redox network followed by drug/radiation assessment. The approach has the dual advantage of identifying potential clinical applications as well as

Free radicals and signal transduction/gene expression

The eukaryotic cell contains a multitude of pathways coupling environmental stimuli to the specific regulation of gene expression. These signals eventually are communicated into the nucleus resulting in the transcription activation and the expression of a series of downstream genes responding to the initial cellular insult. Changes in the pattern of gene expression through ROS-sensitive regulatory transcription factors are crucial components of the machinery that determine the cellular

Imaging redox status in vivo

Given the complexities of determining the redox state of the tumor microenvironment from tumor biopsies as discussed earlier, it would be beneficial if there were means to noninvasively determine the redox status. A novel type of imaging is currently under development, which makes use of nitroxide paramagnetic probes coupled with electron paramagnetic resonance (EPR). The basis for this imaging is that nitroxides, which are detectable by EPR, are reduced once administered to animals to

Conclusions

It is apparent that oxidative stress can initiate molecular signaling pathways, damage molecules, and alter cellular redox. Although the cellular redox system is complex and intricate, continued research of its various components singly and in the context of the complete redox network will yield valuable information that may be translated into a clinical setting.

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