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Research ArticleArticle

Therapeutic Potential of Nitric Oxide-Modified Drugs in Colon Cancer Cells

Marija Mojic, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Djordje Miljkovic, Stanislava Stosic-Grujicic, Marija Stankovic, Katia Mangano, Salvatore Travali, Marco Donia, Paolo Fagone, Mai-Britt Zocca, Yousef Al-Abed, James A. McCubrey and Ferdinando Nicoletti
Molecular Pharmacology October 2012, 82 (4) 700-710; DOI: https://doi.org/10.1124/mol.112.077842
Marija Mojic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Sanja Mijatovic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Danijela Maksimovic-Ivanic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Djordje Miljkovic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Stanislava Stosic-Grujicic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Marija Stankovic
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Katia Mangano
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Salvatore Travali
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Marco Donia
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Paolo Fagone
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Mai-Britt Zocca
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Yousef Al-Abed
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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James A. McCubrey
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Ferdinando Nicoletti
Department of Immunology, Institute for Biological Research “Sinisa Stankovic” (M.M., S.M., D.M.-I., D.M., S.S.-G.) and Institute of Molecular Genetics and Genetic Engineering (M.S.), Belgrade University, Belgrade, Serbia (M.S.); Department of Biomedical Sciences, University of Catania, Catania, Italy (K.M., S.T., M.D., P.F.); OncoNOx Aps, Copenhagen, Denmark (M.-B.Z., F.N.); Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Health System, Long Island, New York (Y.A.-A.); and Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina (J.A.M.)
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Abstract

We have examined the influence of the nitric oxide (NO)-modified anti-inflammatory drug (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) named GIT-27NO or the NO-modified antiviral drug saquinavir (Saq) named Saq-NO on two colon cancer cell lines, mouse CT26CL25 and human HCT116. The effects of the drugs on cell viability, apoptosis, proliferation, and metastatic potential were analyzed. The release of NO and oxygen and nitrogen species was also determined. The efficacy of the drugs was evaluated in vivo in BALB/c mice injected with CT26CL25 cells. Both agents suppressed the growth of colon cancer cells in vitro and reduced tumor volume in syngeneic BALB/c mice. However, their mechanisms of action were different because GIT-27NO released larger amounts of nitrite than Saq-NO in cell cultures and its antitumor action depended on the intracellular NO release inside the cells. On the contrary, Saq-NO released barely detectable amounts of NO and its antitumor action was NO-independent. In fact, cotreatment with an NO-peroxynitrite scavenger revealed that GIT-27NO but not Saq-NO acts through peroxynitrite-mediated cell destruction. At the cellular level, GIT-27NO prevalently induced proapoptotic signals followed by caspase-dependent apoptosis. In contrast, Saq-NO blocked cell proliferation, changed the adhesive, migratory, and invasive properties of the cells, and decreased metastatic potential in vivo. In conclusion, differences in NO release and oxidative stress generation between GIT-27NO and Saq-NO resulted in different mechanisms that caused cell death.

Footnotes

  • M.D., M.B.Z., Y.A.-A. and F.N. are shareholders of OncoNOx.

  • This work was supported in part by the Serbian Ministry of Education and Science [Grant 173013].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.077842.

  • ABBREVIATIONS:

    NSAID
    nonsteroidal anti-inflammatory drug
    NO
    nitric oxide
    VGX-1027
    (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid
    ROS
    reactive oxygen species
    RNS
    reactive nitrogen species
    Saq
    saquinavir
    DETA NONOate
    diethylenetriamine NONOate
    MEG sulfate
    (2-mercaptoethyl)-guanidine sulfate
    SNAP
    S-nitroso-N-acetyl-d,l-penicillamine
    SIN-1 chloride
    linsidomine
    AnnV
    annexin V-FITC
    PCR
    polymerase chain reaction
    PBS
    phosphate-buffered saline
    SNP
    sodium nitroprusside
    CV
    crystal violet
    DHR
    dihydrorhodamine 123
    PI
    propidium iodide
    p
    phospho
    PI3K
    phosphatidylinositol 3-kinase.

  • Received January 19, 2012.
  • Accepted July 13, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
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1 Oct 2012
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Research ArticleArticle

GIT-27NO and Saq-NO Suppressed Colon Cancer Growth

Marija Mojic, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Djordje Miljkovic, Stanislava Stosic-Grujicic, Marija Stankovic, Katia Mangano, Salvatore Travali, Marco Donia, Paolo Fagone, Mai-Britt Zocca, Yousef Al-Abed, James A. McCubrey and Ferdinando Nicoletti
Molecular Pharmacology October 1, 2012, 82 (4) 700-710; DOI: https://doi.org/10.1124/mol.112.077842

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Research ArticleArticle

GIT-27NO and Saq-NO Suppressed Colon Cancer Growth

Marija Mojic, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Djordje Miljkovic, Stanislava Stosic-Grujicic, Marija Stankovic, Katia Mangano, Salvatore Travali, Marco Donia, Paolo Fagone, Mai-Britt Zocca, Yousef Al-Abed, James A. McCubrey and Ferdinando Nicoletti
Molecular Pharmacology October 1, 2012, 82 (4) 700-710; DOI: https://doi.org/10.1124/mol.112.077842
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