S. Mijatovic and D. Maksimovic-Ivanic contributed equally to this work.
Original Research Article
Article first published online: 19 APR 2011
Copyright © 2010 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 226, Issue 7, pages 1803–1812, July 2011
How to Cite
Mijatovic, S., Maksimovic-Ivanic, D., Mojic, M., Timotijevic, G., Miljkovic, D., Mangano, K., Donia, M., Di Cataldo, A., Al-Abed, Y., Cheng, K. F., Stosic-Grujicic, S. and Nicoletti, F. (2011), Cytotoxic and immune-sensitizing properties of nitric oxide-modified saquinavir in iNOS-positive human melanoma cells. J. Cell. Physiol., 226: 1803–1812. doi: 10.1002/jcp.22513
YAL and FN are shareholders of GaNiAl Immunotherapeutics, Inc. No competing conflict of interest exist for the other authors.
- Issue published online: 19 APR 2011
- Article first published online: 19 APR 2011
- Accepted manuscript online: 10 NOV 2010 12:00AM EST
- Manuscript Accepted: 19 OCT 2010
- Manuscript Received: 4 JUN 2010
- Serbian Ministry of Science. Grant Number: 143029
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. © 2010 Wiley-Liss, Inc.