Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells

Catherine Adams, Helen O. McCarthy, Jonathan A. Coulter, Jenny Worthington, Claire Murphy, Tracy Robson, Davi G. Hirst

    Research output: Contribution to journalArticle

    29 Citations (Scopus)

    Abstract

    Background Nitric oxide (NO center dot) derived from donor drugs has been shown to be an effective chemosensitizer in vitro. We investigated the combination of inducible nitric oxide synthase (iNOS) gene transfer, driven by a strong constitutive promoter (cytomegalovirus; CMV) with the DNA cross-linking agent cisplatin in mouse and human tumour cell lines. Methods Proof of principal experiments were performed in the radiation-induced fibrosarcoma-1 (RIF-1) murine cell line. Cells were transfected with constitutively expressed CMV/iNOS plasmid DNA using a cationic lipid vector, before exposure to cisplatin. In vivo efficacy was determined in an intradermal RIF-1 turnout model, with intraperitoneal administration of cisplatin. Additionally, treatment potential was investigated in various human turnout cell lines including human prostate (DU145 and PC3) and human colon (HT29 and HCT116) cancer cell lines. Experimental endpoints were established using western blot, Greiss test, clonogenic assay and turnout growth delay. Results Transfection of RIF-1 turnout cells in vitro with the CMV/iNOS significantly enhanced the cytotoxicity of cisplatin (0.2-1.0 PM). In vivo transfer of CMV/iNOS by direct injection into established RIF-1 tumours caused a significant (p = 0.0027) delay in turnout growth. CMV/iNOS gene transfer in vitro resulted in the strong expression of iNOS DNA in all cell lines, and significantly increased levels of NO center dot in all cell lines except HCT116. Conclusions Significant chemosensitization of cisplatin cytotoxicity was observed in the presence of NO center dot derived from the overexpression iNOS. We conclude that p53 status of the various cell lines was unlikely to be responsible for cisplatin-induced apoptosis. Copyright (C) 2008 John Wiley & Sons, Ltd.
    LanguageEnglish
    Pages160-168
    JournalJournal of Gene Medicine
    Volume11
    Issue number2
    DOIs
    Publication statusPublished - Feb 2009

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    Nitric Oxide Synthase Type II
    Nitric Oxide Synthase
    Genetic Therapy
    Cisplatin
    Fibrosarcoma
    Cell Line
    Neoplasms
    Radiation
    DNA
    HCT116 Cells
    Growth
    Tumor Cell Line
    Cytomegalovirus
    Genes
    Transfection
    Prostate
    Nitric Oxide
    Colon
    Plasmids
    Western Blotting

    Cite this

    Adams, C., McCarthy, H. O., Coulter, J. A., Worthington, J., Murphy, C., Robson, T., & Hirst, D. G. (2009). Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells. Journal of Gene Medicine, 11(2), 160-168. https://doi.org/10.1002/jgm.1280
    Adams, Catherine ; McCarthy, Helen O. ; Coulter, Jonathan A. ; Worthington, Jenny ; Murphy, Claire ; Robson, Tracy ; Hirst, Davi G. / Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells. In: Journal of Gene Medicine. 2009 ; Vol. 11, No. 2. pp. 160-168.
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    title = "Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells",
    abstract = "Background Nitric oxide (NO center dot) derived from donor drugs has been shown to be an effective chemosensitizer in vitro. We investigated the combination of inducible nitric oxide synthase (iNOS) gene transfer, driven by a strong constitutive promoter (cytomegalovirus; CMV) with the DNA cross-linking agent cisplatin in mouse and human tumour cell lines. Methods Proof of principal experiments were performed in the radiation-induced fibrosarcoma-1 (RIF-1) murine cell line. Cells were transfected with constitutively expressed CMV/iNOS plasmid DNA using a cationic lipid vector, before exposure to cisplatin. In vivo efficacy was determined in an intradermal RIF-1 turnout model, with intraperitoneal administration of cisplatin. Additionally, treatment potential was investigated in various human turnout cell lines including human prostate (DU145 and PC3) and human colon (HT29 and HCT116) cancer cell lines. Experimental endpoints were established using western blot, Greiss test, clonogenic assay and turnout growth delay. Results Transfection of RIF-1 turnout cells in vitro with the CMV/iNOS significantly enhanced the cytotoxicity of cisplatin (0.2-1.0 PM). In vivo transfer of CMV/iNOS by direct injection into established RIF-1 tumours caused a significant (p = 0.0027) delay in turnout growth. CMV/iNOS gene transfer in vitro resulted in the strong expression of iNOS DNA in all cell lines, and significantly increased levels of NO center dot in all cell lines except HCT116. Conclusions Significant chemosensitization of cisplatin cytotoxicity was observed in the presence of NO center dot derived from the overexpression iNOS. We conclude that p53 status of the various cell lines was unlikely to be responsible for cisplatin-induced apoptosis. Copyright (C) 2008 John Wiley & Sons, Ltd.",
    author = "Catherine Adams and McCarthy, {Helen O.} and Coulter, {Jonathan A.} and Jenny Worthington and Claire Murphy and Tracy Robson and Hirst, {Davi G.}",
    year = "2009",
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    doi = "10.1002/jgm.1280",
    language = "English",
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    Adams, C, McCarthy, HO, Coulter, JA, Worthington, J, Murphy, C, Robson, T & Hirst, DG 2009, 'Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells', Journal of Gene Medicine, vol. 11, no. 2, pp. 160-168. https://doi.org/10.1002/jgm.1280

    Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells. / Adams, Catherine; McCarthy, Helen O.; Coulter, Jonathan A.; Worthington, Jenny; Murphy, Claire; Robson, Tracy; Hirst, Davi G.

    In: Journal of Gene Medicine, Vol. 11, No. 2, 02.2009, p. 160-168.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells

    AU - Adams, Catherine

    AU - McCarthy, Helen O.

    AU - Coulter, Jonathan A.

    AU - Worthington, Jenny

    AU - Murphy, Claire

    AU - Robson, Tracy

    AU - Hirst, Davi G.

    PY - 2009/2

    Y1 - 2009/2

    N2 - Background Nitric oxide (NO center dot) derived from donor drugs has been shown to be an effective chemosensitizer in vitro. We investigated the combination of inducible nitric oxide synthase (iNOS) gene transfer, driven by a strong constitutive promoter (cytomegalovirus; CMV) with the DNA cross-linking agent cisplatin in mouse and human tumour cell lines. Methods Proof of principal experiments were performed in the radiation-induced fibrosarcoma-1 (RIF-1) murine cell line. Cells were transfected with constitutively expressed CMV/iNOS plasmid DNA using a cationic lipid vector, before exposure to cisplatin. In vivo efficacy was determined in an intradermal RIF-1 turnout model, with intraperitoneal administration of cisplatin. Additionally, treatment potential was investigated in various human turnout cell lines including human prostate (DU145 and PC3) and human colon (HT29 and HCT116) cancer cell lines. Experimental endpoints were established using western blot, Greiss test, clonogenic assay and turnout growth delay. Results Transfection of RIF-1 turnout cells in vitro with the CMV/iNOS significantly enhanced the cytotoxicity of cisplatin (0.2-1.0 PM). In vivo transfer of CMV/iNOS by direct injection into established RIF-1 tumours caused a significant (p = 0.0027) delay in turnout growth. CMV/iNOS gene transfer in vitro resulted in the strong expression of iNOS DNA in all cell lines, and significantly increased levels of NO center dot in all cell lines except HCT116. Conclusions Significant chemosensitization of cisplatin cytotoxicity was observed in the presence of NO center dot derived from the overexpression iNOS. We conclude that p53 status of the various cell lines was unlikely to be responsible for cisplatin-induced apoptosis. Copyright (C) 2008 John Wiley & Sons, Ltd.

    AB - Background Nitric oxide (NO center dot) derived from donor drugs has been shown to be an effective chemosensitizer in vitro. We investigated the combination of inducible nitric oxide synthase (iNOS) gene transfer, driven by a strong constitutive promoter (cytomegalovirus; CMV) with the DNA cross-linking agent cisplatin in mouse and human tumour cell lines. Methods Proof of principal experiments were performed in the radiation-induced fibrosarcoma-1 (RIF-1) murine cell line. Cells were transfected with constitutively expressed CMV/iNOS plasmid DNA using a cationic lipid vector, before exposure to cisplatin. In vivo efficacy was determined in an intradermal RIF-1 turnout model, with intraperitoneal administration of cisplatin. Additionally, treatment potential was investigated in various human turnout cell lines including human prostate (DU145 and PC3) and human colon (HT29 and HCT116) cancer cell lines. Experimental endpoints were established using western blot, Greiss test, clonogenic assay and turnout growth delay. Results Transfection of RIF-1 turnout cells in vitro with the CMV/iNOS significantly enhanced the cytotoxicity of cisplatin (0.2-1.0 PM). In vivo transfer of CMV/iNOS by direct injection into established RIF-1 tumours caused a significant (p = 0.0027) delay in turnout growth. CMV/iNOS gene transfer in vitro resulted in the strong expression of iNOS DNA in all cell lines, and significantly increased levels of NO center dot in all cell lines except HCT116. Conclusions Significant chemosensitization of cisplatin cytotoxicity was observed in the presence of NO center dot derived from the overexpression iNOS. We conclude that p53 status of the various cell lines was unlikely to be responsible for cisplatin-induced apoptosis. Copyright (C) 2008 John Wiley & Sons, Ltd.

    U2 - 10.1002/jgm.1280

    DO - 10.1002/jgm.1280

    M3 - Article

    VL - 11

    SP - 160

    EP - 168

    JO - Journal of Gene Medicine

    T2 - Journal of Gene Medicine

    JF - Journal of Gene Medicine

    SN - 1099-498X

    IS - 2

    ER -

    Adams C, McCarthy HO, Coulter JA, Worthington J, Murphy C, Robson T et al. Nitric oxide synthase gene therapy enhances the toxicity of cisplatin in cancer cells. Journal of Gene Medicine. 2009 Feb;11(2):160-168. https://doi.org/10.1002/jgm.1280