Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.
2019
Authors:
Paskaš, SvetlanaKrajnović, Tamara
Basile, Maria S.
Dunđerović, Duško
Cavalli, Eugenio
Mangano, Katia
Mammana, Santa
Al-Abed, Yousef
Nicoletti, Ferdinando
Mijatović, Sanja
Maksimović-Ivanić, Danijela
Document Type:
Article (Accepted Version)
,
© 2019 Wiley Periodicals, Inc.
Metadata
Show full item recordAbstract:
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.
Keywords:
HIV-protease inhibitors; Ritonavir; Melanoma; SenescenceSource:
Molecular Carcinogenesis, 2019Funding / projects:
- Molecular mechanisms of physiological and pharmacological control of inflammation and cancer (RS-MESTD-Basic Research (BR or ON)-173013)
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
DOI: 10.1002/mc.23020
PubMed: 30997718
WoS: 000474276900003
Scopus: 2-s2.0-85064600105
URI
https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.23020https://radar.ibiss.bg.ac.rs/handle/123456789/3339