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Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo.
- Source :
-
Investigational new drugs [Invest New Drugs] 2019 Oct; Vol. 37 (5), pp. 1014-1028. Date of Electronic Publication: 2019 Feb 01. - Publication Year :
- 2019
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 37
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 30706336
- Full Text :
- https://doi.org/10.1007/s10637-019-00733-3