Open Access Dissertation
Date of Award
Stanley R. Terlecky
Peroxisomes are important regulators of cellular redox balance and function as a signaling platform to regulate anti-aging metabolic and communication networks. In addition the organelle has emerged as a major player in maintaining cellular ROS at an optimal level. At such levels, these ROS are involved in initiation of signaling cascades and that produce an array of anti-aging and disease processes. However, as cells age over time, ROS amass within the peroxisome and elsewhere in the cell. This leads to an imbalance in oxidative homeostasis and results in compromised signaling networks. The goal of this dissertation was to treat disease cell models with a targeted antioxidant approach to help elucidate its biological effects and the extent to which reprograming the cellular redox environment contributes to cellular homeostasis.
There have been many studies involving antioxidant therapies; however, for the most part, these approaches have not been successful. We would argue this is due to their non-selective, non-targeted natures. In contrast, we have chosen to examine a selective and carefully targeted antioxidant - CAT-SKL. It is our contention that this molecule efficiently and safely targets oxidative stress, chronic inflammation, and resultant pro-aging and pro-disease pathways initiated in cells. CAT-SKL is designed to enter cells by virtue of a cell penetrating peptide. Once inside, presumably mediated by an endocytic event, it is directed to the peroxisome via its peroxisomal targeting signal, SKL, and metabolizes H2O2 within the organelle and elsewhere in the cell.
In conditions where H2O2 and related ROS are unchecked, their accumulation leads to a pro-aging cascade and the onset of disease. Maintaining cellular redox balance and degrading pro-inflammatory mediators within the peroxisome is essential for normal cellular function. By specifically targeting this organelle and restoring peroxisomal catalase in a number of disease cells, CAT-SKL may represent a major therapeutic advance. This enzyme has provided important results with respect to several major disease models. In a breast cancer model the drug sensitizes otherwise resistant human breast cancer cells to the TKI, gefitinib; in a diabetic retinopathy model, CAT-SKL significantly reverses compromised retinal function; and in a rat cell model of Alzheimer's disease, β-amyloid peptide-induced neuronal toxicity is significantly reduced.
Giordano, Courtney Rose, "Effects Of Altering The Peroxisomal Redox State In Models Of Degenerative Disease" (2014). Wayne State University Dissertations. 986.