Sensitizing activities of nitric oxide donors for cancer resistance to anticancer therapeutic drugs

Cancer is not a single disease but it constitutes a large variety of different types that are also different from each other phenotypically and molecularly. Although the standard treatments have resulted in clinical responses in a subset of patients, though, many patients relapse and no longer respond to further treatments. Hence, both the innate and adaptive resistance to treatments are the main challenges in today's treatment strategies. Noteworthy, several novel treatment strategies, particularly immunotherapies, used alone or in combination, have been developed and that have significantly improved the therapeutic response of many unresponsive cancer patients. Nevertheless, even with the latest new developments of therapeutics that were effective in a larger subset of patients, there is still an urgent need to treat the remaining unresponsive subset of patients. This requires the development of new targeting agents of superior antitumor activities that will lead to overcoming the unaffected resistance by current treatments. There has been accumulating evidence suggesting nitric oxide donors as such targeting agents and considering their pleiotropic antitumor activities, including both the reversal of chemo and immuno-resistance of various unresponsive resistant cancers. The in vitro and in vivo preclinical findings corroborate the sensitizing antitumor activities of nitric oxide donors. In addition, a few clinical findings with NO donors that have been applied in patients have corroborated their antitumor and sensitizing activities in combination with standard therapies. In this review, the role and underlying mechanisms by which nitric oxide donors sensitize cancer resistant cells to both chemotherapy and immunotherapy are briefly described.