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: Sanja Mijatovic, Danijela Maksimovic-Ivanic, Marija Mojic, Graziella Malaponte, Massimo Libra, Vera Cardile, Djordje Miljkovic, Ljubica Harhaji, Darrin Dabideen, Kai Fan Cheng, Ylenia Bevelacqua, Marco Donia, Gianni Garotta, Yousef Al-Abed, Stanislava Stosic-Grujicic, Ferdinando Nicoletti
• Journal: Nitric oxide : biology and chemistry (Nitric Oxide) Vol. 19 Issue 2 Pg. 177-83 (Sep 2008) ISSN: 1089-8611 [Electronic] United States
• PMID: 18460348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-phenyl-4,5-dihydro-5-isoxazole acetic acid
• Acetates
• Antineoplastic Agents
• Nitric Oxide Donors
• Oxazoles
• Tumor Suppressor Protein p53
• YY1 Transcription Factor

Topics

• Acetates
• Antineoplastic Agents
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Humans
• Melanoma (drug therapy, pathology)
• Nitric Oxide Donors (pharmacology, therapeutic use)
• Oxazoles
• Tumor Suppressor Protein p53 (drug effects)
• YY1 Transcription Factor (antagonists & inhibitors)