The Implications of Reactive Oxygen Species or Free Radicals on the Cancer Formation and Prevention Yavuz Cakir, Ph.D. Dep of BCEHS Biology Benedict College.
Download ReportTranscript The Implications of Reactive Oxygen Species or Free Radicals on the Cancer Formation and Prevention Yavuz Cakir, Ph.D. Dep of BCEHS Biology Benedict College.
The Implications of Reactive Oxygen Species or Free Radicals on the Cancer Formation and Prevention Yavuz Cakir, Ph.D. Dep of BCEHS Biology Benedict College Free Radicals Molecules that have unpaired electrons -shown by a on the structure or chemical symbol O2 - superoxide, NO nitric oxide Essential for normal physiology Side products from oxygen metabolism Not all are, unstable, highly reactive or toxic Oxidants Capable of adding oxygen or taking away hydrogen from a molecule. NAD NADH May or may not be free radicals Some of the Biologically Relevant Players (ROS and RNS)… • Nitric oxide (.NO) .- • Superoxide (O2 ) • Hydrogen peroxide (H2O2) • Peroxynitrite (ONOOH) • Organic peroxides (ROOH) . • Peroxyl radical (ROO ) • Hypochlorous Acid (HOCl) . • Hydroxyl Radicals ( OH) .• Ubisemiquinone (UBSQ ) . NO and O2.- are the fundamental “building blocks” for the majority of “free radicals” Some sources of free radicals • Nitric oxide synthase (NOS) • Superoxide dismutase (SOD) • NADPH oxidase • Xanthine oxidase (XO) • Myeloperoxidase (MPO) • Mitochondria Examples of important physiological functions that involve free radicals or their derivatives: •Oxygen diffusion and thus, regulation of functions dependent on oxygen concentration • Electron transport (ATP production) • Signaling (e.g. vascular tone, fatty acid derived signaling molecules) • Pathogen killing • Pathology of chronic disease • Xenobiotic toxicity Oxidative Stress Increased mtDNA and nDNA damage. Altered mitochondrial and cellular enzyme activities. Increased nitration and oxidation of mitochondrial and cellular proteins. Oxidative Stress Reactive oxygen species or Free Radicals are formed as a natural consequence of a variety of essential biochemical reactions. • Cellular oxidases • Electron transport • Nitric oxide synthases Antioxidants act to inactivate or remove reactive species. • Superoxide dismutase • Catalase • Glutathione peroxidase Antioxidants The Resultant Oxidant Load (Stress) is the Balance between Antioxidants and Oxidants Antioxidants Oxidants The balance between oxidants and antioxidants will dictate cellular levels of oxidative stress, and thus, damage Some Sources of Oxidative Stress: Extrinsic Factors Alcohol Smoking Hypercholesterolemia Diabetes Hypertension Stress Intrinsic Factors Membraneassociated Oxidases (NADPH Oxidase) “Signaling” Oxidative Stress e– Cellular Oxidases (Xanthine oxidase, cyclooxygenase) OXPHOS MPO NOS ATP Some Enzymatic sources of ROS production and clearance NAD(P)H oxidases O2 XO SOD .O2 catalase H2O2 H2O GSH peroxidase hypoxanthine xanthine xanthine uric acid MPO Cl- GSH H 2 O + O2 GSSG HOCl GSH reductase Cakir Y, 2005 NADP+ NADPH Cytokine action (e.g. TNF-a, PDGF), environmental stress “Signaling” ATP H+ H+ H+ ADP H+ Cyt C I III Ubiq II mtDNA NAD O2 GSH H2O2 ONOO- GRed H2O ADP FADH2 NADP ANT V FAD O2.- NADH IV ROS ATP ADP .NO GPx GSSG NADPH CO2 H2O CA Cycle Damage, dysfunction, apoptosis Cakir Y, 2005 Aconitase ONOOCO2- Oxidative Injury Hypothesis One of the key steps in cancer is the oxidation of the proteins and enzymes: Oxidant Stress -P ox-P Whereas oxidation of proteins can occur by a number of processes, they all will have increased oxidant production in common: • Membrane associated oxidases • Inflammatory response • Cytokines • Programmed cell death • Mitochondria Oxidative metabolism is critical to the preservation of cellular function Human Disease Processes Mediated by Free Radicals Free Radicals Normal Oxidized In the biological sense, oxidant damage occurs when genetic material, lipids, and proteins are oxidized so that their normal function is altered • CNS • Aging • Chronic inflammation • Cardiovascular disease • Cancer • Diabetes Antioxidants in the cell Membranes Vitamin E Ubiquinol Mitochondria MnSOD GSH, GPX Cytosol Cu/Zn SOD, Catalase GSH, GPX Superoxide Levels Superoxide Levels Knight-Lozano CA et al. Circulation. 2002;105(7):849-854 Nitrotyrosine Levels Nitration Levels Lung Cancer 30 mg/m3 TSP – Normal Cells + – + ETS Exposure Increases mtDNA Damage 2.5 P = 0.011 MtDNA lesions/16.0 kb 2.0 1.5 1.0 0.5 0.0 Filtered Air ETS Mitochondrial Complex I Activity 80 nmol/min/mg protein 60 P < 0.05 Filtered Air CS 40 20 0 Exposure Mitochondrial Complex IV Activity 50 40 30 20 10 0 P < 0.05 mmol/min/mg protein 90 80 70 60 Filtered Air CS Exposure Summary: •Oxidation: •increases the formation diseases •causes mtDNA damage •decreases the functions of mt enzymes •increases formation of Free Radicals • Mitochondria appear to be vulnerable to prolonged increases in oxidative and nitrosoxidative stress • Its beneficial and deleterious effects may be modulated by antioxidants • Several human diseases can be related to altered oxidant regulation •How can we protect ourselves from the effects of ROS?