Redox imbalance and biochemical changes in cancer

Abstract

For this article, we explore a hypothesis involving the possible role of reduction/oxidation (redox) state in cancer. We hypothesize that many modifications in cellular macromolecules, observed in cancer progression, may be caused by redox imbalance. Recent biochemical data suggest that human prostate cancer cell lines show a redox imbalance (oxidizing) compared with benign primary prostate epithelial cells; the degree of oxidation varied with aggressive behavior of each cell line. Our recent data suggest that human breast cancer tissues show a redox imbalance (reducing) compared with benign adjacent breast tissues. Accumulating data summarized in this article suggest that redox imbalance may regulate gene expression and alter protein stability by posttranslational modifications, in turn modulating existing cellular programs. Despite significant improvements in cancer therapeutics, resistance occurs, and redox imbalance may play a role in this process. Studies show that some cancer therapeutic agents increase generation of reactive oxygen/nitrogen species and antioxidant enzymes, which may alter total antioxidant capacity, cause cellular adaptation, and result in reduced effectiveness of treatment modalities. Approaches involving modulations of intra- and extracellular redox states, in combination with other therapies, may lead to new treatment options, especially for patients who are resistant to standard treatments.

Figure 1

The reduced form of TRX1 was predominant in human breast cancer tissues. The redox state of TRX1 was quantified relative to total TRX1 and demonstrated a 4.7-fold significant increase (p ≦ 0.04) * expressed as the reduced form of TRX1 relative to total in infiltrating ductal carcinomas (cancer) versus benign/adjacent tissues (benign). Data from paired tissues obtained on biopsy or mastectomy were averaged from two patients from the University of Wisconsin School of Medicine and Public Health and two from Capital Biosciences. Redox western blotting involves derivatization of proteins with a thiol-reactive reagent such as iodoacetic acid (IAA), followed by native gel electrophoresis and western blotting.

Figure 2

Human breast cancer tissues demonstrated increased TRX activities. Data demonstrated a 2.1-fold increased trend in TRX activities in infiltrating ductal carcinomas (cancer) versus benign/adjacent tissues (benign). Paired tissues obtained on biopsy/mastectomy from six patients were obtained from the University of Wisconsin School of Medicine and Public Health and Capital Biosciences. The insulin disulfide reduction assay was utilized to assess total TRX activity of six paired human tissues relative to GAPDH in triplicate. The assay measures the rate of which TRX (1 × 10 ⁻⁸ M TRX) catalyzes reduction of insulin disulfides by dithiothreitol.