The induction of NO in tumor cells or exogenous NO donors reverse tumor cell resistance and chemo-immuno-sensitize the cells to apoptosis. The inhibition of the repressor YY1 by NO results in the upregulation of Fas and DR5 expressions on tumor cells and their sensitization to FasL, TRAIL and chemotherapeutic-induced apoptosis.

The mechanism by which NO mediates its sensitization is a result of its interference on the dysregulated pro-survival/anti-apoptotic NF-κΒ /Snail/YY1/RKIP/PTEN loop in tumor cells.

NO interference is the result of its direct inhibition of NF-κΒ, Snail, and YY1 and the induction of RKIP.

The inhibition of the repressor Snail and YY1 by NO results in the induction of RKIP and PTEN and inhibition of the pro-survival/anti-apoptotic NF-κΒ and AKT pathways, respectively.

NO donors are potential therapeutic agents to reverse resistance and to inhibit EMT and metastasis when used in combination with subtoxic chemo-immuno-cytotoxic agents.