Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

Abstract

Significance: Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency. Recent Advances: Ionizing radiation (IR)-generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from cell death to development of radioresistance. Critical Issues: Tumors are heterogeneous and dynamic communication occurs between stromal and prostate cancer cells, and complicated redox-regulated mechanisms exist in the tumor microenvironment. Thus, antioxidant and anti-inflammatory strategies should be carefully evaluated for each patient at different stages of the disease to maximize therapeutic benefits while minimizing unintended side effects. Future Directions: Compared with normal cells, tumor cells are usually under higher oxidative stress and secrete more proinflammatory mediators. Thus, redox status is often less adaptive in tumor cells than in their normal counterparts. This difference can be exploited in a search for new cancer therapeutics and treatment regimes that selectively activate cell death pathways in tumor cells with minimal unintended consequences in terms of chemo-and radio-resistance in tumor cells and toxicity in normal tissues. Antioxid. Redox Signal. 20, 1481-1500.

Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A

“…Redox homeostasis is an essential albeit delicate balance as excess ROS can result in apoptotic cell death [ 31 ]. Most cancer cells are at a higher oxidative state than their normal counterparts [ 42 – 44 ] thus, an increase in ROS would therefore push cancer cells beyond the toxic threshold [ 44 , 45 ]. It is known that cancer cells adapt to this increased oxidative state by upregulating their antioxidant capacity, which decreases their ability to regulate further changes in oxidative stress compared to normal cells [ 44 , 46 ].…”

Selenium as an adjuvant for modification of radiation response

“…However, studies have revealed that high doses of ionizing radiation may stimulate chronic oxidative stress because of endogenous production of ROS and nitric oxide (NO) by macrophages, lymphocytes, as well as some pro-oxidants, such as nicotinamide adenine dinucleotide phosphate oxidase in other cells. [21][22][23] Activation of pro-oxidant enzymes and also mitochondria produce large amounts of ROS and NO that are able to overcome the antioxidant defense system of cells including superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT). 24 Chronic oxidative stress leads to continuous DNA damage, cell death, inflammation, and increased risk of carcinogenesis.…”

Radiation resistance: Cancer stem cells (CSCs) and their enigmatic pro-survival signaling

“…Finally peroxisomes, intracellular respiratory organelles, also generate intracellular ROS. The ROS play important physiological roles (in cell proliferation, differentiation, metabolism, cell death, tumorigenesis, cell-cell adhesion, and cell motility [40,41]); intracellular ROS levels are permanently regulated by ROS scavengers [14,37]. Various families of enzymes act to reduce the concentration of ROS: these include superoxide dismutase [42], superoxide reductase [38], catalase [43], glutathione peroxidase [44], glutathione reductase [38] and the multifunctional protein apurinic/apirimidinic endonuclease/redox effector factor (Ape1/Ref-1, also known as APEX1) [45].…”