ECB-ART-47136
Redox Biol
2019 Oct 01;27:101190. doi: 10.1016/j.redox.2019.101190.
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S-nitrosothiols and H2S donors: Potential chemo-therapeutic agents in cancer.
Reis AKCA
,
Stern A
,
Monteiro HP
.
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Nitric Oxide (NO) and Hydrogen Sulfide (H2S) are components of an "interactome", which is defined as a redox system involving the interactions of RSS, RNS and ROS. Chemical interaction by these species is common and is characterized by one and two electron oxidation, nitrosylation, nitration and sulfuration/polysulfidation reactions. NO and H2S are gases that penetrate cell membranes, are synthesized by specific enzymes, are ubiquitous, regulate protein activities through post-translational modifications and participate in cell signaling. The two molecules at high concentrations compared to physiological concentrations may result in cellular damage particularly through their interaction with other reactive species. NO and H2S can interact with each other and form a variety of molecular species which may have constructive or destructive behavior depending on the cell type, the cellular environment (ex. oxygen tension, pH, redox state), where the products are produced and in what concentrations. Cross talk exists between NO and H2S, whereby they can influence the generation and signaling behavior of each other. Given the above mentioned properties of NO and H2S and studies in cancer cells and animal models employing NO and H2S donors that generate higher than physiological concentrations of NO and H2S and are effective in killing cancer cells but not normal cells, lend credence to the possibility of the utility of these donors in an approach to the treatment of cancer.
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Genes referenced: LOC100888042 LOC105443556 LOC115919910 LOC576378 LOC579267 LOC591290 LOC752031 ros1 sgpl1 sod1
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Fig. 1. Conformational structures of the S-nitrosothiol-derivatives of penicillamine. A. S-Nitroso-N-Acetylpenicillamine – SNAP. B. S-Nitroso-Aryl-Butanamide – 1(Y = H). C. p-methoxy- S-Nitroso-Aryl-Butanamide – 2(Y = p-OMe). D. o-chloro- S-Nitroso-Aryl-Butanamide – 3(Y = o-Cl). E. m-chloro- S-Nitroso-Aryl-Butanamide – 4(Y = m-Cl). Calculations of the S-N bond length for SNAP and for the S-nitroso-aryl-butanamides yield a value of 1.7 Å, which gives these compounds relative stability and NO releasing capacity. |
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Fig. 2. Biosynthesis of nitric oxide and hydrogen sulfide, generation of reactive oxygen species, and redox homeostasis. A. NO is produced by three nitric oxide synthase (NOS) isoforms: two constitutive isoforms, NOS-1 and NOS-3, and one inducible, NOS-2 catalyzes the oxidation of l-arginine to l-citrulline. NOS-2 is widely expressed in tumor cells and NOS-2 alternative splicing isoforms potentially regulate negatively intracellular NO levels in these cells. Negative regulation of NO production is also achieved through the upregulation of arginase. B. Reactive oxygen species (ROS) are produced through activation of the NADPH oxidase (NOX) enzymes or through leakage of the mitochondrial electron transport chain which releases O2−. O2- is dismutated to H2O2 by Superoxide Dismutases (SOD) and H2O2 is reduced to H2O by Catalase, maintaining intracellular optimal levels of the reactive species. C. H2S is generated from oxidation of l-cysteine and other substrates, including 3-mercaptopyruvate. Two cytoplasmic enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) and two mitochondrial enzymes 3-mercaptopyruvate sulfur-transferase (3-MST) and Cysteine aminotransferase (Cys-AT) are responsible for intracellular generation of H2S. H2S can be converted into polysulfide and other reactive sulfur species (RSS). SOD and Catalase may help in the maintenance of optimal intracellular levels of RSS. |
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Fig. 3. Proposed mechanism for nitrosative stress in tumor cells exposed to a combination of SNO donors and H2S. The SNO donor SNO-Aryl-butanamide nitrosylates Cys generating CysNO. CysNO directly enters the cell through an amino-acid transporter (LAT). SNO-Aryl-butanamide reacts with H2S generating HSNO which freely diffuses into the cell. CysNO and HSNO nitrosylate GSH and protein thiols promoting nitrosative stress and tumor cell apoptosis. |
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