Apoptosis-Inducing High (NO)-N-center dot Concentrations Are Not Sustained Either in Nascent or in Developed Cancers

作者：Heller Adam^*

来源：ChemMedChem, 2008, 3(10): 1493-1499.

DOI：10.1002/cmdc.200800257

• cancer
• inhibitors
• iNOS expression
• nitric oxide
• angiogenesis
• arginine depletion

Nitric oxide ((NO)-N-center dot) induces apoptosis at high concentrations by S-nitrosating proteins such as glyceraldehyde-3-phosphate dehydrogenase. This literature analysis revealed that failure to sustain high (NO)-N-center dot concentrations is common to all cancers. In cervical, gastric, colorectal, breast, and lung cancer, the cause of this failure is the inadequate expression of inducible nitric oxide synthase (iNOS), resulting from the inhibition of iNOS expression by TGF-beta 1 at the mRNA level. In bladder, renal, and prostate cancer, the reason for the insufficient (NO)-N-center dot levels is the depletion of arginine, resulting from arginase overexpression. Arginase competes with iNOS for arginine, catalyzing its hydrolysis to ornithine and urea. In gliomas and ovarian sarcomas, low (NO)-N-center dot levels are caused by inhibition of iNOS by N-chlorotaurine, produced by infiltrating neutrophils. Stimulated neutrophils express myeloperoxidase, catalyzing H2O2 oxidation of Cl- to HOCl, which N-chlorinates taurine at its concentration of 19 mm in neutrophils. In squamous cell carcinomas of the skin, ovarian cancers, lymphomas, Hodgkin's disease, and breast cancers, low (NO)-N-center dot concentrations arise from the inhibition of iNOS by N-bromotaurine, produced by eosinophil-peroxidase-expressing infiltrating eosinophils. Eosinophil peroxidase catalyzes the H2O2 oxidation of Br- to HOBr which N-brominates taurine to N-bromotaurine at its concentration of 15 mm in eosinophils. In micro vascularized tumors, the (NO)-N-center dot concentration is further depleted; (NO)-N-center dot is rapidly consumed by red blood cells (RBCs) through S-nitrosation of RBC glutathione and hemoglobin; and by oxidation to nitrate by RBC oxyhemoglobin. Angiogenesis-inhibiting antibodies are currently used to treat cancers; their mode of action is not, as previously thought, reduction of the tumor O-2 or nutrient supply. They actually decrease the loss of (NO)-N-center dot to RBCs.

• 出版日期2008-10