title: The NO-modified HIV protease inhibitor as a valuable drug for hematological malignancies: Role of p70S6K.
abstract: Covalent attachment of NO to the first approved HIV protease inhibitor Saquinavir (Saq-NO) expands the therapeutic potential of the original drug. Apart from retained antiviral activity, the modified drug exerts strong antitumor effects and lower toxicity. In the present study, we have evaluated the sensitivity of different hematological malignancies to Saq-NO. Saq-NO efficiently diminished the viability of Jurkat, Raji, HL-60 and K562 cells. While Jurkat and Raji cells (established from pediatric patients) displayed abrogated proliferative potential, HL-60 and K652 cells (originated from adults) exposed to Saq-NO treatment underwent caspase dependent apoptosis. In addition, similar sensitivity to Saq-NO was observed in mononuclear blood cells obtained from pediatric patients with acute lymphoblastic leukemia (ALL) and adult patients with acute myeloid leukemia (AML). Western blot analysis indicated p70S6 kinase as a possible intracellular target of Saq-NO action. Moreover, the addition of a NO moiety to Lopinavir resulted in improved antitumor potential as compared to the parental compound, suggesting that NO-derived HIV protease inhibitors are a potential new source of anticancer drugs with unique mode of action.
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", Belgrade University, Belgrade, Serbia.
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimovic-Ivanic
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", Belgrade University, Belgrade, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Mojic
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", Belgrade University, Belgrade, Serbia.
authors.forename: Mirna
authors.initials: M
authors.lastname: Bulatovic
authors.affiliation: Clinical Center "Dr Dragisa Misovic", Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Radojkovic
authors.affiliation: Institute for Health Care of Mother and Child of Serbia "Dr Vukan Cupic", Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: Milos
authors.initials: M
authors.lastname: Kuzmanovic
authors.affiliation: Clinical Center "Dr Dragisa Misovic", Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Ristic
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", Belgrade University, Belgrade, Serbia.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", Belgrade University, Belgrade, Serbia.
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljkovic
authors.affiliation: Department of Biomedical Sciences and Biotechnology, University of Catania, Catania, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cavalli
authors.affiliation: Department of Biomedical Sciences and Biotechnology, University of Catania, Catania, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.affiliation: Department of Biomedical Sciences and Biotechnology, University of Catania, Catania, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
authors.forename: James
authors.initials: J
authors.lastname: McCubrey
authors.affiliation: Department of Biomedical Sciences and Biotechnology, University of Catania, Catania, Italy. Electronic address: ferdinic@unict.it.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", Belgrade University, Belgrade, Serbia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatovic
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology; D009569:Nitric Oxide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects*; D019258:Saquinavir / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017320:HIV Protease Inhibitors; D009569:Nitric Oxide; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D019258:Saquinavir
keywords: Acute lymphoid leukemia; Acute myeloid leukemia; Saquinavir; Saquinavir-NO; p70S6 kinase