Free Radicals In Carcinogenesis And Apoptosis The Critical Balance

Under normal physiological conditions, ROS and RNS play a role in signal transduction and gene transcription in cells. Nitric oxide (NO) generated by activated macrophages is an important mediator of immune response. NO produced in the nervous system by neurons acts as a neurotransmitter. In addition, NO produced by the endothelial cells is essential for regulating vascular tone and vasodilation besides the relaxation and proliferation of vascular smooth muscle cells, leukocyte adhesion, platelet aggregation, and angiogenesis.

ROS trigger carcinogenesis by causing permanent DNA damage and also mutations in p53, as observed in skin, hepatocellular, and colon carcinoma. Insufficient repak of DNA causes a procarcinogenic response, triggering selection of cancerous cells and angiogenesis. ROS also modulate the activity of several transcription factors, such as the NF-kB and AP-1 pathways that regulate the Jun and c-Fos oncoproteins. In M14

melanoma cells,"! and H202 are reported to enhance tumor growth by inactivation of SH groups of caspases that regulate apoptosis.114 All these are involved in initiation, promotion, and progression of carcinogenesis (Figure 13.2).4 However, ROS can have a diametrically opposite effect and suppress or inhibit carcinogenesis (Figure 13.2). Generation of adequate amounts of ROS triggers tumor cell apoptosis by enhancing p53 expression and telomere shortening. Telomeres regulate cell division, and in human somatic cells, telomeres shorten with each cell division. However in tumors, telomeres are stabilized at constant length by the enzyme telomerase.115 H2O2 treatment of nonproliferating human MRC-5 fibroblasts was reported to accelerate the shortening of telomeres and reduce cell growth and differentiation.116

Thus, low concentrations of ROS such as H2O2 promote cell proliferation, while intermediate doses result in growth arrest. However ROS generated in large amounts cause the oxidation of biomolecules such as amino acids, proteins, lipids, and DNA, which leads to cell injury and death. Aerobic organisms adapt to the oxidative shoes by increasing the production of glutathione,

FREE RADICALS {Ertfogcrous or pcrsislent exposure)

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