Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.

Abstract

The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.

• Authors: Svetlana Paskaš, Tamara Krajnović, Maria S Basile, Duško Dunđerović, Eugenio Cavalli, Katia Mangano, Santa Mammana, Yousef Al-Abed, Ferdinando Nicoletti, Sanja Mijatović, Danijela Maksimović-Ivanić
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 58 Issue 8 Pg. 1362-1375 (08 2019) ISSN: 1098-2744 [Electronic] United States
• PMID: 30997718 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Actins
• HIV Protease Inhibitors
• Lipofuscin
• Reactive Oxygen Species
• TP53 protein, human
• Tubulin
• Tumor Suppressor Protein p53
• Vinculin
• Ribosomal Protein S6 Kinases
• beta-Galactosidase
• Ritonavir

Topics

• Actins (biosynthesis)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects)
• HIV Protease Inhibitors (pharmacology)
• Humans
• Lipofuscin (metabolism)
• Melanoma (drug therapy, pathology)
• Reactive Oxygen Species (metabolism)
• Ribosomal Protein S6 Kinases (antagonists & inhibitors)
• Ritonavir (pharmacology)
• Tubulin (biosynthesis)
• Tumor Suppressor Protein p53 (biosynthesis)
• Vinculin (biosynthesis)
• beta-Galactosidase (metabolism)