1. Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo.
- Author
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Paskas S, Mazzon E, Basile MS, Cavalli E, Al-Abed Y, He M, Rakocevic S, Nicoletti F, Mijatovic S, and Maksimovic-Ivanic D
- Subjects
- Animals, Autophagy, Drug Hypersensitivity, Female, Humans, In Vitro Techniques, Melanoma metabolism, Melanoma pathology, Mice, Mice, Inbred C57BL, Mice, Nude, Reactive Oxygen Species metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Apoptosis drug effects, Cell Proliferation drug effects, HIV Protease Inhibitors pharmacology, Lopinavir pharmacology, Melanoma drug therapy, Nitric Oxide metabolism
- Abstract
We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.
- Published
- 2019
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