title: A photodynamic bifunctional conjugate for prostate cancer: an in vitro mechanistic study.
abstract: Photodynamic therapy (PDT) has drawn considerable attention for its efficacy against certain types of cancers. It shows however limits in the case of deep cancers, favoring tumor recurrence under suboptimal conditions. More insight into the molecular mechanisms of PDT-induced cytotoxicity and cytoprotection is essential to extend and strengthen this therapeutic modality. As PDT induces iNOS/NO in both tumor and microenvironment, we examined the role of nitric oxide (NO) in cytotoxicity and cytoprotection. Our findings show that NO mediates its cellular effects by acting on the NF-κB/YY1/RKIP loop, which controls cell growth and apoptosis. The cytoprotective effect of PDT-induced NO is observed at low NO levels, which activate the pro-survival/anti-apoptotic NF-κB and YY1, while inhibiting the anti-survival/pro-apoptotic and metastasis suppressor RKIP. In contrast, high PDT-induced NO levels inhibit NF-κB and YY1 and induce RKIP, resulting in significant anti-tumor activity. These findings reveal a critical role played by NO in PDT and suggest that the use of bifunctional PDT agents composed of a photosensitizer and a NO-donor could enhance the photo-treatment effect. A successful application of NO in anticancer therapy requires control of its concentration in the target tissue. To address this issue we propose as PDT agent, a bimolecular conjugate called DR2, composed of a photosensitizer (Pheophorbide a) and a non-steroidal anti-androgen molecule capable of releasing NO under the exclusive control of light. The mechanism of action of DR2 in prostate cancer cells is reported and discussed.
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy. valentina.rapozzi@uniud.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Rapozzi
authors.affiliation: Institute of Organic Synthesis and Photoreactivity, Italian National Research Council, Via P. Gobetti 101, 40129, Bologna, Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Varchi
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Della Pietra
authors.affiliation: Institute of Organic Synthesis and Photoreactivity, Italian National Research Council, Via P. Gobetti 101, 40129, Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ferroni
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy.
authors.forename: Luigi E
authors.initials: LE
authors.lastname: Xodo
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014226:Triazenes / Q000494:pharmacology*; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D016328:NF-kappa B; D020030:Nitric Oxide Donors; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D017319:Photosensitizing Agents; D014226:Triazenes; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D002734:Chlorophyll; D009569:Nitric Oxide; C032623:pheophorbide a
keywords: Cell tumor recurrence; DR2 conjugate; NF-κB/YY1/RKIP loop; Nitric oxide; Photodynamic therapy; Prostate cancer cells