Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo
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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.
KeywordsHIV protease inhibitors Lopinavir Nitric oxide Trans-differentiation Melanoma Schwann-like cells
The work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia [grant number 173013] and by the current research funds (2018) of IRCCS Centro Neurolesi “Bonino–Pulejo”, Messina, Italy.
Compliance with ethical standards
Conflicts of interest
Svetlana Paskas declares that she has no conflicts of interest. Emanuela Mazzon declares that she has no conflicts of interest. Maria Sofia Basile declares that she has no conflicts of interest. Eugenio Cavalli declares that he has no conflicts of interest. Yousef Al-Abed is a cofounder and shareholder of OncoNOx, which has outlicensed lopinavir-NO to Inflamalps.
Mingzhu He declares that she has no conflicts of interest. Sara Rakocevic declares that she has no conflicts of interest. Ferdinando Nicoletti is a cofounder and shareholder of OncoNOx, which has outlicensed lopinavir-NO to Inflamalps. Sanja Mijatovic declares that she has no conflicts of interest. Danijela Maksimovic-Ivanic declares that she has no conflicts of interest.
This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Animal studies were performed in accordance with local guidelines and approved by the local Institutional Animal Care and Use Committee (IACUC), approval nr. 01–08/17.
For this type of study, formal consent is not required.
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