Chemoprotective And Chemosensitizing Effects Of Nitric Oxide And Other Biologically Active Gases In Breast Cancer Chemotherapy: Potential Implications

Since the discovery in 1987 that vascular endothelial cells are able to synthesize nitric oxide (NO) from L-arginine, the existence of this biochemical pathway in many other cell types has been thoroughly documented, and its relevance in biology has become apparent. NO, a free-radical gas, synthesized by a family of isoenzymes called NO synthases, was shown to play a key role as a cell-signaling molecule in the vascular nervous and immune systems. It also exhibited a cytostatic/cytotoxic property at higher concentrations as generated by activated macrophages and endothelial cells. The role of NO in cancer biology and more so in breast cancer, however, started to be elucidated only in 1995 by Thomsen et al. (1995). In this chapter, we will review some of the key aspects of endogenous NO as produced in breast cancer cells and breast tumors. We will allude to the early studies that described NO production in breast tumor tissues and breast cancer cells and point to some of its proposed functions in breast cancer homeostasis. We will discuss how these findings could be of therapeutic benefit and finally end with some information on how a mechanistic cross talk between endogenously produced NO and another gaseous signaling molecule, hydrogen sulfide (H2S), in breast cancer cells may open up new opportunities for intervention. We will also discuss one potential mechanism of infiltration of tumor-associated macrophages in breast cancer and its clinical significance.