Danijela Maksimovic-Ivanic, Sanja Mijatovic, Djordje Miljkovic, Ljubica Harhaji-Trajkovic, Gordana Timotijevic, Marija Mojic, Darrin Dabideen, Kai Fan Cheng, James A. McCubrey, Katia Mangano, Yousef Al-Abed, Massimo Libra, Gianni Garotta, Stanislava Stosic-Grujicic, Ferdinando Nicoletti
Abstract
Application of the HIV protease inhibitor saquinavir (Saq) to cancer chemotherapy is limited by its numerous side effects. To overcome this toxicity, we modified the original compound by covalently attaching a nitric oxide (NO) group. We compared the efficacy of the parental and NO-modified drugs in vitro and in vivo. The novel compound saquinavir-NO (Saq-NO) significantly reduced the viability of a wide spectrum of human and rodent tumor cell lines at significantly lower concentration than the unmodified drug. In contrast to Saq, Saq-NO had no effect on the viability of primary cells and drastically reduced B16 melanoma growth in syngeneic C57BL/6 mice. In addition, at the equivalent of the 100% lethal dose of Saq, Saq-NO treatment caused no apparent signs of toxicity. Saq-NO blocked the proliferation of C6 and B16 cells, up-regulated p53 expression, and promoted the differentiation of these two cell types into oligodendrocytes or Schwann-like cells, respectively. Although it has been well documented that Saq decreases tumor cell viability by inhibiting Akt, the anticancer properties of Saq-NO were completely independent of the phosphatidylinositol 3-kinase/Akt signaling pathway. Moreover, Saq-NO transiently up-regulated Akt phosphorylation, delivering a protective signal that could be relevant for primary cell protection and the absence of drug toxicity in vivo. It was unlikely that released NO was independently responsible for these drug effects because Saq-NO treatment increased intracellular and secreted NO levels only slightly. Rather, the chemical modification seems to have produced a qualitatively new chemical entity, which may have a unique mode of action against cancer cells.
This research output has an Altmetric Attention Score of 9. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 08 October 2015.
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#3,272,848
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#506
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#11,427
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Outputs of similar age from Molecular Cancer Therapeutics
#6
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Altmetric has tracked 22,792,160 research outputs across all sources so far. Compared to these this one has done well and is in the 84th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 3,861 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.2. This one has done well, scoring higher than 82% of its peers.
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We're also able to compare this research output to 55 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 81% of its contemporaries.
