Asian women nonsmokers with NSCLC have a high rate of EGFR + mutations and they have a better prognosis also. Could ROS be the underlying deficiency?
Zhang et al!
"Once thought of as toxic by-products of cellular metabolism, reactive oxygen species (ROS) have been implicated in a large variety of cell-signaling processes. Several enzymatic systems contribute to ROS production in vascular endothelial cells, including NA(D)PH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase, and the mitochondrial electron transport chain. The respiratory chain is the major source of ROS in most mammalian cells, but the role of mitochondria-derived ROS in vascular cell signaling has received little attention. A new paradigm has evolved in recent years postulating that, in addition to producing ATP, mitochondria also play a key role in cell signaling and regulate a variety of cellular functions. This review focuses on the emerging role of mitochondrial ROS as signaling molecules in vascular endothelial cells. Specifically, we discuss some recent findings that indicate that mitochondrial ROS regulate vascular endothelial function, focusing on major sites of ROS production in endothelial mitochondria, factors modulating mitochondrial ROS production, the physiological and clinical implications of endothelial mitochondrial ROS, and methodological considerations in the study of mitochondrial contribution to vascular ROS generation."
WIKIPEDIA!
" Normally, cells defend themselves against ROS damage with enzymes such as alpha-1-microglobulin, superoxide dismutases, catalases, lactoperoxidases, glutathione peroxidases and peroxiredoxins. Small molecule antioxidants such as ascorbic acid (vitamin C), tocopherol (vitamin E), uric acid, and glutathione also play important roles as cellular antioxidants. In a similar manner, polyphenol antioxidants assist in preventing ROS damage by scavenging free radicals. In contrast, the antioxidant ability of the extracellular space is less - e.g., the most important plasma antioxidant in humans is uric acid."
WHAT IS THE AFFECTED WOMEN'S LEVEL OF URIC ACID?
ARE THESE WOMEN TAKING A URICOSURIC?
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UNDER HYPOXIC CONDITIONS, LACK OF ATP AND DECREASED coQ, A DANGER START GROWING IN THE MITOCHONDRIA, SUPEROXIDE ARE BUILDING UP AND UNLESS CONDITIONS CHANGE OR UNLESS THE ABOVE ENZYMES INTERVENE TO DILUTE THE SITUATION, THE OXIDE FREE RADICAL WILL SPILL OVER THE CYTOSOL (CYTOCHROME B WILL ALSO BE INVOLVED) WHERE THEY WILL OXYDIZE VARIOUS MOLECULES AND INDUCE INFLAMMATORY AND POTENTIALLY NEOPLASTIC PROCESSES!
" In general, harmful effects of reactive oxygen species on the cell are most often:[4]
- damage of DNA
- oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation)
- oxidations of amino acids in proteins
- oxidatively inactivate specific enzymes by oxidation of co-factors"
Metabolic adaptation in tumours balances the cells' need for energy with equally important need for macromolecular building blocks and tighter control of redox balance. As a result, production of NADPH is greatly enhanced, which functions as a cofactor to provide reducing power in many enzymatic reactions for macromolecular biosynthesis and at the same time rescuing the cells from excessive ROS produced during rapid proliferation. Cells counterbalance the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX), which rely on the reducing power of NADPH to maintain their activities.[19]
Most risk factors associated with cancer interact with cells through the generation of ROS. ROS then activate various transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), hypoxia-inducible factor-1α and signal transducer and activtor of transcription 3 (STAT3), leading to expression of proteins that control inflammation; cellular transformation; tumor cell survival; tumor cell proliferation; and invasion, agiogenesis as well as metastasis. And ROS also control the expression of various tumor supressor genes such as p53, retinoblastoma gene (Rb), and phosphatase and tensin homolog (PTEN).[20]"
HOW THESE DRAMATIC EVENTS IMPACT THE MUC GENES FAMILY AND EGFR HAS NOT BEEN DESCRIBED FULLY AND COULD EXPLAIN HOW IN THE LUNG, AN ADENOCARCINOMA COULD RESULT. THE GOOD RESPONSE TO ANTI EGFR POINT TO A SINGLE CAUSAL EVENT THAT IS REVERSED OR ATTENUATED BY INITIATION OF TARCEVA AND RELATED MOLECULES. BEING MITOCHONDRIAL, IT MAY BE A CLUE TO MTOR INHIBITOR ACTIVITY AFTER FAILURE OF EGFR (SECOND LINE AS DISCUSSED PREVIOULSY)
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