Just Say NO to Cancer?

Extract

In this issue of the Journal, Xie and co-workers ( 1 ) demonstrate that introducing nitric oxide (NO) synthase type II (NOSII, iNOS) into tumor cells produces cytotoxicity not only in the transfected cells but also in bystander tumor cells. Here, we discuss the potential implications of these experiments in the light of present knowledge on the complex role of NO in tumor biology.

The growth of solid tumors is regulated by interactions betweenen do the lial cells of the tumor vasculature, tumor infiltrating immune cells (such as T lymphocytes and macrophages), and the tumor cells themselves. In these cellular interactions, the unusual biologic messenger molecule and cytotoxin, NO, may play important pathobiologic roles in addition to its many physiologic functions ( 2 ). Endogenous NO production from l -arginine has been directly or indirectly demonstrated in all of these cell types. In most cases, the inducible NO synthasegene (Nos2)—one of three known human Nos genes ( 3 )—was switched on (presumably by NF-κB-dependent mechanisms). Its gene product, the high-output NOS-II isoform, unlike its constitutively expressed low-output counterparts (NOS-I and-III), is not regulated by the intracellular concentration of free calcium ( 3 ) and is chronically active. Such continuously high exposure of cells to endogenous NO as well as exogenous NO donors will inhibit proliferation and induce cell death ( 4 ). High NO levels inhibit mitochondrial respiration, the citric acid cycle, glycolysis, and DNA replication. Locally high levels of reactive oxygen species (ROS), stemming, for example, from host immune cells or from an insufficient oxygen supply to the tumor tissue, may exacerbate these toxic effects by generating even more reactive compounds, such as peroxynitrite (ONOO ⁻ ). The latter compound arises from the diffusion-limited interaction of NO and O ₂⁻ and is even more reactive than NO, but it is stable enough to diffuse to and thus harm tumor cells.