Anticancer and Differentiation Properties of the Nitric Oxide Derivative of Lopinavir in Human Glioblastoma Cells
Maria Sofia Basile,
Emanuela Mazzon,
Tamara Krajnovic,
Dijana Draca,
Eugenio Cavalli,
Yousef Al-Abed,
Placido Bramanti,
Ferdinando Nicoletti,
Sanja Mijatovic,
Danijela Maksimovic-Ivanic
Affiliations
Maria Sofia Basile
Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, Belgrade University, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Emanuela Mazzon
IRCCS Centro Neurolesi Bonino Pulejo, Strada Statale 113, C.da Casazza, 98124 Messina, Italy
Tamara Krajnovic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, Belgrade University, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Dijana Draca
Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, Belgrade University, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Eugenio Cavalli
IRCCS Centro Neurolesi Bonino Pulejo, Strada Statale 113, C.da Casazza, 98124 Messina, Italy
Yousef Al-Abed
Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community drive, Manhasset, NY 11030, USA
Placido Bramanti
IRCCS Centro Neurolesi Bonino Pulejo, Strada Statale 113, C.da Casazza, 98124 Messina, Italy
Ferdinando Nicoletti
Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy
Sanja Mijatovic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, Belgrade University, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Danijela Maksimovic-Ivanic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, Belgrade University, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Glioblastoma (GBM) is the most frequent and deadly form of primary malignant brain tumor among adults. A promising emerging approach for GBM treatment may be offered from HIV protease inhibitors (HIV-PIs). In fact, in addition to their primary pharmacological activity in the treatment of HIV infection, they possess important anti-neoplastic effects. According to previous studies, the addition of a nitric oxide (NO) donating group to parental compounds can reduce their toxicity and enhance the anticancer action of various compounds, including HIV-PIs. In this study we compared the effects of the HIV-PI Lopinavir (Lopi) and of its NO-derivative Lopinavir-NO (Lopi-NO) on the in vitro growth of LN-229 and U-251 human GBM cell lines. Lopi-NO reduced the viability of LN-229 and U-251 cells at significantly lower concentrations than the parental drug. In particular, Lopi-NO inhibited tumor cell proliferation and induced the differentiation of U-251 cells toward an astrocyte-like phenotype without triggering significant cell death in both cell types. The anticancer effect of Lopi-NO was persistent even upon drug removal. Furthermore, Lopi-NO induced strong autophagy that did not appear to be related to its chemotherapeutic action. Overall, our results suggest that Lopi-NO could be a potential effective anticancer drug for GBM treatment.
