Title |
Cytotoxic and immune‐sensitizing properties of nitric oxide‐modified saquinavir in iNOS‐positive human melanoma cells
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Published in |
Journal of Cellular Physiology, April 2011
|
DOI | 10.1002/jcp.22513 |
Pubmed ID | |
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 |
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. |
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