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Review
. 2015 Dec:6:486-494.
doi: 10.1016/j.redox.2015.08.013. Epub 2015 Aug 18.

Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics

Benjamin Bonavida  1 , Hermes Garban  2
Affiliations
Review

Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics

Benjamin Bonavida et al. Redox Biol. 2015 Dec.

Abstract

The generation of NO by the various NO synthases in normal and malignant tissues is manifested by various biological effects that are involved in the regulation of cell survival, differentiation and cell death. The role of NO in the cytotoxic immune response was first revealed by demonstrating the induction of iNOS in target cells by immune cytokines (e.g. IFN-γ, IL-1, TNF-α, etc.) and resulting in the sensitization of resistant tumor cells to death ligands-induced apoptosis. Endogenous/exogenous NO mediated its immune sensitizing effect by inhibiting NF-κΒ activity and downstream, inactivating the repressor transcription factor YY1, which inhibited both Fas and DR5 expressions. In addition, NO-mediated inhibition of NF-κΒ activity and inhibition downstream of its anti-apoptotic gene targets sensitized the tumor cells to apoptosis by chemotherapeutic drugs. We have identified in tumor cells a dysregulated pro-survival/anti-apoptotic loop consisting of NF-κB/Snail/YY1/RKIP/PTEN and its modification by NO was responsible, in large, for the reversal of chemo and immune resistance and sensitization to apoptotic mechanisms by cytotoxic agents. Moreover, tumor cells treated with exogenous NO donors resulted in the inhibition of NF-κΒ activity via S-nitrosylation of p50 and p65, inhibition of Snail (NF-κΒ target gene), inhibition of transcription repression by S-nitrosylation of YY1 and subsequent inhibition of epithelial-mesenchymal transition (EMT), induction of RKIP (inhibition of the transcription repressor Snail), and induction of PTEN (inhibition of the repressors Snail and YY1). Further, each gene product modified by NO in the loop was involved in chemo-immunosensitization. These above findings demonstrated that NO donors interference in the regulatory circuitry result in chemo-immunosensitization and inhibition of EMT. Overall, these observations suggest the potential anti-tumor therapeutic effect of NO donors in combination with subtoxic chemo-immuno drugs. This combination acts on multiple facets including reversal of chemo-immune resistance, and inhibition of both EMT and metastasis.

Keywords: Apoptosis; Chemotherapeutic drugs; Nitric oxide; Nitrosylation; Sensitization; Trail DR5.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
NO donors convert the anti-apoptotic NF-κB/Snail/YY1/RKIP/PTEN resistant loop into a sensitive pro-apoptotic loop. The schematic diagram represents tumor cells that have a dysregulated NF-κB/Snail/ YY1/RKIP/PTEN resistant loop involved in the maintenance of the tumor cell viability, proliferation, resistance, EMT, and metastasis. Hence, in tumor cells, the expression and the activities of NF-κB, Snail, YY1 are upregulated while those of RKIP and PTEN are downregulated. The loop is the result of NF-κB-mediated activation of its target Snail and YY1 and, in turn, Snail represses RKIP and YY1 represses PTEN. In addition, YY1 activates Snail. In the presence of NO donors, the activities of NF-κB, Snail and YY1 are inhibited and resulting in the de-repression of RKIP and PTEN. In turn, RKIP potentiates its inhibitory activity on NF-κB and its targets and, likewise, PTEN inhibits the PI3K/Akt pathway which controls NF-κB. Overall, the NO treatment inhibits tumor cell viability, proliferation and sensitizes the cells to chemo-immunotherapies-induced apoptosis.
Fig. 2
Fig. 2
Mechanism of NO-mediated chemo-immunosensitization of resistant tumor cells to apoptosis. The schematic diagram represents the NO-mediated effects that results in the sensitization of resistant tumor cells to drug-immune-induced apoptosis. Both NO donors and iNOS induction will result in the upregulation of NO, resulting in the upregulation of death receptors and sensitization to death ligands (FasL, TRAIL, TNF-α) and activation of the effector caspase 3 and downstream apoptosis. Also, NO will inhibit anti-apoptotic gene products such as Bcl-2 and allowing cytotoxic drugs to act on the mitochondrial membrane and resulting on the activation of caspase 3 or induction of AIF, all of which result in apoptosis.
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