Therapeutic potential for coxib-nitric oxide releasing hybrids in cancer treatment.

In the last three decades, several experimental evidences pointed out the involvement of chronic inflammation in promoting the development of cancer, supporting all stages of tumorigenesis, tumor growth, and spread. In addition, the importance of the tumor microenvironment, an indispensable participant for tumor establishment and growth, turned out by highlighting the important role that stromal and inflammatory cells have in orchestrating the promotion of tumor cells proliferation, survival, and migration. The relationship between inflammation and cancer, the underlying mechanisms, the cells involved, as well as the corresponding crosstalks are, herein, briefly reviewed. In particular, the effects mediated by cyclooxygenase-2 (COX-2) and corresponding product prostaglandin (PG) E2 on tumor growth and tumor immune evasion are discussed along with corresponding molecular mechanisms. Immunotherapy has become a milestone in cancer treatment, strikingly improving life expectancy of patients with a broad variety of malignancies while dramatically reducing the side effects of the therapy. The progresses obtained with immunotherapy (in particular with Programmed cell deth protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors) in cancer treatment are briefly reviewed along with the underlying mechanisms. The effects exerted by the COX-2/PGE2 axis on PD-1/PD-L1 expression, and more in general on the immune system, are discussed. The clinical investigations on cancer prevention of nonsteroidal antiinflammatory drugs and corresponding results are herein commented along with the side effects that hampered the clinical trials. The outcome obtained with NO-releasing drugs in overcoming these side effects is commented in comparison with the corresponding results obtained with the NO-donor COX-2 inhibitors that we have developed. Moreover, the effect that NO release may have on tumor initiation, growth, and metastasis as well as in controlling immunosuppression is briefly reviewed. Taking into account the issues discussed above, we think that the NO-donor COX-2 inhibitor (12e) (VA694) and corresponding backups can be good candidates for further studies as therapeutic agents for cancer treatment, either in combination with immune checkpoint (PD-1/PD-L1) inhibitors or with standard chemotherapy.