Figure 7.

Proposed mechanisms involved in inhibiting tumor cell metabolism after co-cultivation of tumor cells with NO-generating activated macrophages. Cytokines and other agents (LPS, IFNγ, STAT1, and TNF-α, etc.) promote the synthesis of iNOS-derived NO in macrophages [16]. NO can then diffuse from the cell or form a DNIC complex and be actively transported out of the cell [132,135]. NO is transported into the target tumor cell via diffusion or actively by protein disulfide isomerase (PDI) through trans-nitrosylation [177]. NO within cells has several physiological effects [178,179] and can react with iron and GSH to create DNICs. MRP1 functions to export DNICS out of the cell to facilitate iron and GSH efflux, which results in iron depletion and inhibition of tumor cell proliferation.