The development of cancer cell resistance to various cytotoxic stimuli continues to be a major challenge in oncology and novel therapeutic approaches are urgently needed. Nitric oxide (NO) is emerging as a potential anti-oncogenic agent to overcome tumor cell resistance to conventional therapeutic agents. NO is a ubiquitous, water-soluble, free radical gas that exerts a wide range of biological effects. The actions of nitric oxide are highly variable in oncology with reports in the literature on both sides of the spectrum as an anti-neoplastic vs. a pro-neoplastic agent. The final activity of NO in oncology is dependent on its working microenvironment, including the type of cell exposed to the compound, the redox state of the reaction, as well as the final intracellular concentration and the duration of intracellular exposure to nitric oxide. There is, however, no unifying mechanistic explanation for the biphasic role of nitric oxide in oncology. Nitric oxide donors mimic continuous production of NO in a wide range of time intervals (seconds to days). Thus, multiple biological and (pro- vs. anti-) neoplastic responses are elicited from NO donors depending on the half-life and the type of cell exposed to the compound. The large variety of nitric oxide donors may serve as a tool to explore the wide range of oncologic properties of NO in cancer. In the present report, we discuss classic nitric oxide donors and their potential therapeutic roles as cytotoxic agents or chemo-radio or -immune-sensitizing compounds in the treatment of drug-resistant cancers.

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