Redox regulation in cancer: a double-edged sword with therapeutic potential

Abstract

Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of reactive oxygen species (ROS) and cell's own antioxidant defenses. ROS deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis. Ultraviolet (UV) exposures, gamma-radiation and other environmental carcinogens generate ROS in the cells, which can exert apoptosis in the tumors, thereby killing the malignant cells or induce the progression of the cancer growth by blocking cellular defense system. Cancer stem cells take the advantage of the aberrant redox system and spontaneously proliferate. Oxidative stress and gene-environment interactions play a significant role in the development of breast, prostate, pancreatic and colon cancer. Prolonged lifetime exposure to estrogen is associated with several kinds of DNA damage. Oxidative stress and estrogen receptor-associated proliferative changes are suggested to play important roles in estrogen-induced breast carcinogenesis. BRCA1, a tumor suppressor against hormone responsive cancers such as breast and prostate cancer, plays a significant role in inhibiting ROS and estrogen mediated DNA damage; thereby regulate the redox homeostasis of the cells. Several transcription factors and tumor suppressors are involved during stress response such as Nrf2, NF-kappaB and BRCA1. A promising strategy for targeting redox status of the cells is to use readily available natural substances from vegetables, fruits, herbs and spices. Many of the phytochemicals have already been identified to have chemopreventive potential, capable of intervening in carcinogenesis.

Figure 1

Wt BRCA1 downregulates the production of ROS in MCF-7 breast cancer cells. Cells were transfected either with background vector (pcDNA3) or with wt BRCA1 plasmid. Forty-eight hours post transfection all the cells were treated with 100 µM of ROS producing agent TBHP (tert-butyl hydroperoxide) in a serum free medium. Levels of ROS were detected through confocal microscopy using carboxy-H₂DCF-DA fluorescence (first row). Second row is the phase picture of all the cells that are used for confocal staining. Decrease in the stain intensity in BRCA1 transfected cells compared to vehicle and background vector transfected cells depicts an important function of BRCA1 in protecting cells from oxidative damages.

Figure 2

A putative model for oxidative stress induced interactions in carcinogenesis. Reactive oxygen species (ROS) mediated oxidative stress either by environmental carcinogens such as UV and ionizing radiation or by mitochondrial metabolism exerts several effects on DNA damage and generation of oxidative lesions, gene expression, growth regulation mitogenesis, inflammation, apoptosis and fibrosis leading to genomic instability and cancer progression. Chemical signals generated by dietary chemopreventive agents, anticancer agents, antioxidants and antioxidation enzymes, cause Nrf2 nuclear translocation that sets in motion a dynamic machinery of coactivators and corepressors that might form a multimolecular complex with Nrf2 for modulating transcriptional response through the antioxidant response element, ARE producing several phase II detoxification enzymes as stimulation of cellular defense system during stress. Oxidative stress might also cause release of NFκB from IκB and stimulate NFκB nuclear translocation to modulate transcriptional response through the NFκB response element. Several members of the MAPK family may act in concert with Nrf2 and NFκB with multiple interactions between the members of the putative complex to elicit the chemopreventive and pharmacotoxicological events against carcinogenesis.