@article{
author = "Paskaš, Svetlana and Krajnović, Tamara and Basile, Maria S. and Dunđerović, Duško and Cavalli, Eugenio and Mangano, Katia and Mammana, Sant and Al‐Abed, Yousef and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "The main focus of this study is exploring the effect and mechanism of two HIVprotease
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.",
publisher = "New Jersey: Wiley-VCH Verlag GmbH & Co",
journal = "Molecular Carcinogenesis",
title = "Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma",
number = "8",
volume = "58",
doi = "10.1002/mc.23020",
pages = "1362-1375"
}
