The increasing understanding of the role of nitric oxide (NO) in cancer biology has generated significant progress in the use of NO donor-based therapy to fight cancer. These advances strongly suggest the potential adoption of NO donor-based therapy in clinical practice, and this has been supported by several clinical studies in the past decade. In this review, we first highlight several types of important NO donors, including recently developed NO donors bearing a dinitroazetidine skeleton, represented by RRx-001, with potential utility in cancer therapy. Special emphasis is then given to the combination of NO donor(s) with other therapies to achieve synergy and to the hybridization of NO donor(s) with an anticancer drug/agent/fragment to enhance the activity or specificity or to reduce toxicity. In addition, we briefly describe inducible NO synthase gene therapy and nanotechnology, which have recently entered the field of NO donor therapy.

Different cluster models of isolated Mo VI molybdate species anchored on silica surface were investigated using density functional theory (DFT). Isolated molybdate centers were modeled as either a penta-coordinated mono-oxo species or a tetra-coordinated di-oxo species. Standard free energy changes for interconversion between mono-oxo and di-oxo species indicate that these two species can coexist in equilibrium on the surface of amorphous silica with di-oxo species being the favored species at high temperature and low partial pressures of water. Comparison of Raman-spectra from experiment and DFT suggests that di-oxo species might be the prominent species responsible for the peak at 988 cm -1 . This conclusion is strongly supported by the similarity in the EXAFS spectra obtained from experiment and theory. The thermodynamics for H 2 reduction of isolated molybdate species were determined and found to be in reasonable agreement with experimental observation. DFT calculations of the structure and properties of the reduced Mo IV centers and comparison of these with experimental results suggest that the reduced centers are present as mono-oxo species.

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Nitric oxide (NO) induces a multitude of antitumor activities, encompassing the induction of apoptosis, sensitization to chemo-, radio-, or immune-therapy, and inhibition of metastasis, drug resistance, angiogenesis, and hypoxia, thus attracting much attention in the area of cancer intervention. To improve the precise targeting and treatment efficacy of NO, a glutathione (GSH)-sensitive NO donor (1,5-bis­[(l-proline-1-yl)­diazen-1-ium-1,2-diol-O 2-yl]-2,4-dinitrobenzene, BPDB) coordinates with iron ions to form the nanoscale coordination polymer (NCP) via a simple precipitation and then partial ion exchange process. The obtained Fe­(II)-BNCP shows desirable solubility, biocompatibility, and circulation stability. Quick NO release triggered by high concentrations of GSH in tumor cells improves the specificity of NO release in situ, thus avoiding side effects in other tissues. Meanwhile, under high concentrations of H2O2 in tumors, Fe2+ ions in BPDB-based NCP, named Fe­(II)-BNCP, exert Fenton activity to generate hydroxyl radicals (·OH), which is the main contribution for chemodynamic therapy (CDT). In addition, ·O2 – generated by the Haber-Weiss reaction of Fe2+ ions with H2O2 can quickly react with NO to produce peroxynitrite anion (ONOO–) that is more cytotoxic than ·O2 – or NO only. This synergistic NO-CDT effect has been proved to retard the tumor growth in Heps xenograft ICR mouse models. This work not only implements a synergistic effect of NO-CDT therapy but also offers a simple and efficient strategy to construct a coordination polymer nanomedicine via rationally designed prodrug molecules such as NO donors.

We developed a novel class of hybrids (HP-1a-HP-1f) of telmisartan and 2-(1-hydroxypentyl)-benzoate (HPBA) as a ring-opening derivative of NBP. The most promising hybrid, HP-1c, exhibited more potent anti-inflammatory and neuroprotective effects in vitro and reduced brain infarct volume and improved neurological deficits in a rat model of transient focal cerebral ischemia when compared with telmisartan alone, NBP alone, or a combination of telmisartan and NBP. HP-1c had a therapeutic window of up to 24 h, ameliorated ischemic cerebral injury in permanent focal cerebral ischemia, and improved motor function. The beneficial effects of HP-1c in ischemic stroke were associated with microglial polarization to the M2 phenotype and reduced oxidative stress. HP-1c also shifted the M1/M2 polarization in a mouse neuroinflammatory model. The anti-inflammatory and anti-oxidative effects of HP-1c were associated with AMPK-Nrf2 pathway activation for neuroprotection. We showed that HP-1c penetrates the brain, has a plasma half-life of around 3.93 h, and has no toxicity in mice. Innovation and Conclusion: Our study results suggest that HP-1c, with dual AMPK- and Nrf2-activating properties, may have potential in further studies as a novel therapy for ischemic stroke. Antioxid. Redox Signal. 28, 141-163.