title: Cytotoxic and immune-sensitizing properties of nitric oxide-modified Saquinavir in iNOS-positive human melanoma cells.
abstract: We have recently shown that covalent attachment of the NO moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity. In this study we evaluated the impact of Saq-NO on the growth of A375 human melanoma cells, as a prototype of NO-dependent cancer model. The novel compound strongly affected the in vitro and in vivo progression of A375 melanoma cell growth. The mechanism of antimelanoma action comprised dual drug activity-induction of apoptotic cell death and acquisition of melanoma cell responsiveness to TRAIL. Saq-NO-triggered apoptosis was dependent on transient AKT up-regulation and reduced pERK and iNOS expression that were observed within the first 12 h of exposure to the drug. Thereafter, however, Saq-NO up-regulated both iNOS transcription and NO endogenous synthesis and sensitized A375 cells to TRAIL. Furthermore, reduced YY1 expression was observed after 24 h of Saq-NO exposure, which correlated with increased expression of DR5. The biological relevance of this complex and powerful action of Saq-NO was consistent with the marked drug-induced inhibition of the growth of A375 xenotransplants in nude mice.
authors.affiliation: Department of Immunology, Institute for Biological Research Sinisa Stankovic, Belgrade University, Belgrade, Serbia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatovic
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimovic-Ivanic
authors.forename: Marija
authors.initials: M
authors.lastname: Mojic
authors.forename: Gordana
authors.initials: G
authors.lastname: Timotijevic
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljkovic
authors.forename: Katia
authors.initials: K
authors.lastname: Mangano
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Cataldo
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Kai Fan
authors.initials: KF
authors.lastname: Cheng
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D019258:Saquinavir / Q000031:analogs & derivatives* / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C557004:saquinavir-NO; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019258:Saquinavir