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: Sanja Mijatovic, Danijela Maksimovic-Ivanic, Marija Mojic, Gordana Timotijevic, Djordje Miljkovic, Katia Mangano, Marco Donia, Antonio Di Cataldo, Yousef Al-Abed, Kai Fan Cheng, Stanislava Stosic-Grujicic, Ferdinando Nicoletti
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 226 Issue 7 Pg. 1803-12 (Jul 2011) ISSN: 1097-4652 [Electronic] United States
• PMID: 21506111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• YY1 Transcription Factor
• YY1 protein, human
• saquinavir-NO
• Nitric Oxide
• NOS2 protein, human
• Nitric Oxide Synthase Type II
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Saquinavir

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Male
• Melanoma (drug therapy, enzymology, immunology, pathology)
• Mice
• Mice, Nude
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Saquinavir (analogs & derivatives, pharmacology)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Time Factors
• Up-Regulation
• Xenograft Model Antitumor Assays
• YY1 Transcription Factor (metabolism)