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01.02.2019 | PRECLINICAL STUDIES

Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo

verfasst von: Svetlana Paskas, Emanuela Mazzon, Maria Sofia Basile, Eugenio Cavalli, Yousef Al-Abed, Mingzhu He, Sara Rakocevic, Ferdinando Nicoletti, Sanja Mijatovic, Danijela Maksimovic-Ivanic

Erschienen in: Investigational New Drugs | Ausgabe 5/2019

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Summary

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.

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Titel: Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo
verfasst von: Svetlana Paskas
Emanuela Mazzon
Maria Sofia Basile
Eugenio Cavalli
Yousef Al-Abed
Mingzhu He
Sara Rakocevic
Ferdinando Nicoletti
Sanja Mijatovic
Danijela Maksimovic-Ivanic
Publikationsdatum: 01.02.2019
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 5/2019
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00733-3

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Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo

Summary

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