title: Dual roles of nitric oxide in the regulation of tumor cell response and resistance to photodynamic therapy.
abstract: Photodynamic therapy (PDT) against cancer has gained attention due to the successful outcome in some cancers, particularly those on the skin. However, there have been limitations to PDT applications in deep cancers and, occasionally, PDT treatment resulted in tumor recurrence. A better understanding of the underlying molecular mechanisms of PDT-induced cytotoxicity and cytoprotection should facilitate the development of better approaches to inhibit the cytoprotective effects and also augment PDT-mediated cytotoxicity. PDT treatment results in the induction of iNOS/NO in both the tumor and the microenvironment. The role of NO in cytotoxicity and cytoprotection was examined. The findings revealed that NO mediates its effects by interfering with a dysregulated pro-survival/anti-apoptotic NF-κB/Snail/YY1/RKIP loop which is often expressed in cancer cells. The cytoprotective effect of PDT-induced NO was the result of low levels of NO that activates the pro-survival/anti-apoptotic NF-κB, Snail, and YY1 and inhibits the anti-survival/pro-apoptotic and metastasis suppressor RKIP. In contrast, PDT-induced high levels of NO result in the inhibition of NF-kB, Snail, and YY1 and the induction of RKIP, all of which result in significant anti-tumor cytotoxicity. The direct role of PDT-induced NO effects was corroborated by the use of the NO inhibitor, l-NAME, which reversed the PDT-mediated cytotoxic and cytoprotective effects. In addition, the combination of the NO donor, DETANONOate, and PDT potentiated the PDT-mediated cytotoxic effects. These findings revealed a new mechanism of PDT-induced NO effects and suggested the potential therapeutic application of the combination of NO donors/iNOS inducers and PDT in the treatment of various cancers. In addition, the study suggested that the combination of PDT with subtoxic cytotoxic drugs will result in significant synergy since NO has been shown to be a significant chemo-immunosensitizing agent to apoptosis.
authors: Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy. Electronic address: valentina.rapozzi@uniud.it.
authors: Valentina
authors: V
authors: Rapozzi
authors: Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy. Electronic address: emydellapietra@yahoo.com.
authors: Emilia
authors: E
authors: Della Pietra
authors: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bbonavida@mednet.ucla.edu.
authors: Benjamin
authors: B
authors: Bonavida
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008027:Light; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000378:metabolism; D009928:Organ Specificity; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D020030:Nitric Oxide Donors; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D017319:Photosensitizing Agents; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D009569:Nitric Oxide
keywords: Molecular pathways.; Nitric oxide; Photodynamic therapy; Resistance; Tumor response