title: Novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide (GIT-27NO) induces p53 mediated apoptosis in human A375 melanoma cells.
abstract: In this study we evaluated the effects of the new NO donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide (GIT-27NO) on the A375 human melanoma cell line. Treatment with the drug led to concentration-dependent reduction of mitochondrial respiration and number of viable cells in cultures. Decreased cell viability correlated with release and internalization of NO and was neutralized by the extracellular scavenger hemoglobin. GIT-27NO neither influenced cell division nor induced accidental or autophagic cell death. Early signs of apoptosis were observed upon coculture with the drug, and resulting in marked accumulation of hypodiploid cells, suggesting that the induction of apoptosis is one primary mode of action of the compound in A375 cells. GIT-27NO significantly inhibited the expression of the transcription repressor and apoptotic resistant factor YY1 and, in parallel, augmented the presence of total p53. The capacity of GIT-27NO to induce p53-mediated apoptosis along with inhibition of YY1 repressor in A375 melanoma cells indicates that GIT-27NO possesses an important anti-cancer pharmacological profile. The findings suggest the potential therapeutic use of GIT-27NO in the clinical setting.
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: Graziella
authors.initials: G
authors.lastname: Malaponte
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Vera
authors.initials: V
authors.lastname: Cardile
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljkovic
authors.forename: Ljubica
authors.initials: L
authors.lastname: Harhaji
authors.forename: Darrin
authors.initials: D
authors.lastname: Dabideen
authors.forename: Kai Fan
authors.initials: KF
authors.lastname: Cheng
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Bevelacqua
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Gianni
authors.initials: G
authors.lastname: Garotta
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000085:Acetates; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D010080:Oxazoles; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects*; D050986:YY1 Transcription Factor / Q000037:antagonists & inhibitors
chemical_list: C518641:3-phenyl-4,5-dihydro-5-isoxazole acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D010080:Oxazoles; D016159:Tumor Suppressor Protein p53; D050986:YY1 Transcription Factor