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RESEARCH PRODUCT

Role of Nitric Oxide for Modulation of Cancer Therapy Resistance

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Reactive nitrogen species (RNS) act as central second messengers in a balanced cellular network. While the complexity of nitric oxide (NO) signaling is far from being understood, and many controversial data can be found in the literature, there is evidence for NO as a major player of modulation of resistance to anticancer drugs and radiotherapy. Hypoxia in cancer tissues causes therapy resistance, and the hypoxia-inducing factor-1 (HIF-1) plays a predominant role in hypoxia-induced resistance. NO and NO-donating compounds sensitize tumor cells by inhibiting HIF-1 mediated transcription in hypoxic cells. Among a plethora of other genes, HIF-1-induced the transcription of the multidrug resistance gene 1, MDR1, and the angiogenesis-inducing vascular endothelial growth factor gene (VEGF). NO-mediated down-regulation of glutathione and antioxidant stress response genes as well as the inhibition of DNA repair proteins also contributes to sensitivity of tumors to chemo- and radiotherapy. Hypoxic tumors tend to accumulate cells with mutations in the tumor suppressor gene, TP53. NO activates wild-type p53 protein by peroxynitrite-mediated DNA damage and exerts resistance-modulating effects on wild-type, but not on mutant p53. Furthermore, the antiapoptotic transcription factor, NF-κB, is inhibited by NO and NO donors. Thereby, NO not only enhances susceptibility to anticancer drugs and radiotherapy but also suppresses the NF-κB-mediated transcription of metastasis-regulating genes.