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 Nicoletti, Sanja Mijatovic, Danijela Maksimovic-Ivanic

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1014-1028
Number of pages15
JournalInvestigational New Drugs
Volume37
Issue number5
DOIs
Publication statusPublished - Oct 1 2019

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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