Nitric oxide ((.)NO) 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 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-beta1 at the
mRNA level. In bladder, renal, and
prostate cancer, the reason for the insufficient (.)NO 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 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 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 microvascularized
tumors, the (.)NO concentration is further depleted; (.)NO 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 O2 or nutrient supply. They actually decrease the loss of (.)NO to RBCs.