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Cytotoxic and Immune-Sensitizing Properties of Nitric Oxide-Modified Saquinavir in iNOS-Positive Human Melanoma Cells

2011
Аутори:
Mijatović, Sanja A.
Maksimović-Ivanić, Danijela D.
Mojić, Marija K.
Timotijević, Gordana S
Miljković, Đorđe M.
Mangano, Katia
Donia, Marco
Di Cataldo, Antonio
Al-Abed, Yousef
Cheng, Kai Fan
Stošić-Grujičić, Stanislava D.
Nicoletti, Ferdinando
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Апстракт:
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. J. Cell. Physiol. 226: 1803-1812, 2011. (C) 2010 Wiley-Liss, Inc.
Извор:
Journal of Cellular Physiology, 2011, 226, 7, -1812

ISSN: 0021-9541

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http://ibiss-r.rcub.bg.ac.rs/123456789/1283
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