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

  • Svetlana Paskas
  • Emanuela Mazzon
  • Maria Sofia Basile
  • Eugenio Cavalli
  • Yousef Al-Abed
  • Mingzhu He
  • Sara Rakocevic
  • Ferdinando NicolettiEmail author
  • Sanja Mijatovic
  • Danijela Maksimovic-Ivanic
PRECLINICAL STUDIES
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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.

Keywords

HIV protease inhibitors Lopinavir Nitric oxide Trans-differentiation Melanoma Schwann-like cells 

Notes

Funding

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.

Ethical approval

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.

Informed consent

For this type of study, formal consent is not required.

Supplementary material

10637_2019_733_MOESM1_ESM.jpg (2.6 mb)
Supplement 1 Lopinavir and lopinavir-NO induce a change in the morphology of melanoma cells. Mouse solid melanoma (B16) and mouse metastatic melanoma (B16F10) cells were treated with IC50 concentrations of lopinavir and lopinavir-NO for 48 h and observed under a light microscope (Nikon TS 100, Nikon, Tokyo, Japan); 100X magnification. (JPG 2640 kb)
10637_2019_733_MOESM2_ESM.jpg (1.6 mb)
Supplement 2 Lopinavir and lopinavir-NO induce a minor change in the nuclear morphology in melanoma cells. Mouse solid melanoma (B16) and mouse metastatic melanoma (B16F10) cells were treated with IC50 concentrations of lopinavir and lopinavir-NO for 48 h, stained with propidium iodide and observed under a fluorescence microscope (Axio Observer Z.1, Zeiss, Jena, Germany); 400X magnification. (JPG 1651 kb)
10637_2019_733_MOESM3_ESM.jpg (427 kb)
Supplement 3 Lopinavir-NO releases NO intracellularly. Melanoma cells were incubated with 8 μM lopinavir-NO for the indicated durations. Intracellular NO levels were determined by DAF-FM diacetate staining. The data are presented as the means ± SEMs of three independent experiments. Bars not sharing a common letter indicate significant differences, p < 0.05. (JPG 426 kb)
10637_2019_733_MOESM4_ESM.jpg (349 kb)
Supplement 4 Lopinavir and lopinavir-NO induce oxidative stress, which does not, per se, reduce the viability of melanoma cells. B16 cells were treated with IC50 concentrations of lopinavir and lopinavir-NO (HIV-PIs) in combination with the antioxidant N-acetylcysteine (2.5 μM) for 48 h and stained with crystal violet. The data are presented as the means ± SEMs of three independent experiments. Bars not sharing a common letter indicate significant differences, p < 0.05. (JPG 348 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Svetlana Paskas
    • 1
  • Emanuela Mazzon
    • 2
  • Maria Sofia Basile
    • 1
    • 3
  • Eugenio Cavalli
    • 2
  • Yousef Al-Abed
    • 4
  • Mingzhu He
    • 4
  • Sara Rakocevic
    • 1
  • Ferdinando Nicoletti
    • 3
    Email author
  • Sanja Mijatovic
    • 1
  • Danijela Maksimovic-Ivanic
    • 1
  1. 1.Department of Immunology, Institute for Biological Research “Sinisa Stankovic”Belgrade UniversityBelgradeSerbia
  2. 2.IRCCS Centro Neurolesi “Bonino-Pulejo”MessinaItaly
  3. 3.Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  4. 4.Center for Molecular InnovationThe Feinstein Institute for Medical ResearchManhassetUSA

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