Evaluation of the antiangiogenic potential of AQ4N

Martin O'Rourke, Claire Ward, Jenny Worthington, Julie McKenna, Andrea Valentine, Tracy Robson, David G Hirst, Stephanie McKeown

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Purpose: A number of cytotoxic chemotherapy agents tested at low concentrations show antiangiogenic properties with limited cytotoxicity, e.g., cyclophosphamide, tirapazamine, and mitoxantrone. AQ4N is a bioreductive alkylaminoanthraquinone that is cytotoxic when reduced to AQ4; hence, it can be used to target hypoxic tumor cells. AQ4N is structurally similar to mitoxantrone and was evaluated for antiangiogenic properties without the need for bioreduction.@ Experimental Design: The effect of AQ4N and fumagillin on human microvascular endothelial cells (HMEC-1) was measured using a variety of in vitro assays, i.e., 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound scrape, tubule formation, rat aortic ring, and invasion assays. Low-doseAQ4N (20 mg/kg) was also given in vivo to mice bearing a tumor in a dorsal skin flap.@ Results: AQ4N (10(-11) to 10(-5) mol/L) had no effect on HMEC-1 viability. AQ4N (10(-9) to 10(-5) mol/L) caused a sigmoidal dose-dependent inhibition of endothelial cell migration in the wound scrape model. Fumagillin showed a similar response over a lower dose range (10(-13) to 10(-9) mol/L); however, the maximal inhibition was less (25% versus 43% for AQ4N). AQ4N inhibited HMEC-1 cell contacts on Matrigel (10(-8) to 10(-5) mol/L), HMEC-1 cell invasion, and sprouting in rat aorta explants. Immunofluorescence staining with tubulin, vimentim, dynein, and phalloidin revealed that AQ4N caused disruption to the cell cytoskeleton. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap.@ Conclusions: This combination of assays has shown that AQ4N possesses antiangiogenic effects in normoxic conditions, which could potentially contribute to antitumor activity.
    LanguageEnglish
    Pages1502-1509
    JournalClinical Cancer Research
    Volume14
    Issue number5
    DOIs
    Publication statusPublished - Mar 2008

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    Mitoxantrone
    tirapazamine
    Endothelial Cells
    AQ4N
    Phalloidine
    Dyneins
    Neoplasms
    Skin
    Cytotoxins
    Wounds and Injuries
    Tubulin
    Microvessels
    Cytoskeleton
    Cyclophosphamide
    Cell Movement
    Fluorescent Antibody Technique
    Aorta
    Research Design
    Staining and Labeling
    Drug Therapy

    Cite this

    O'Rourke, M., Ward, C., Worthington, J., McKenna, J., Valentine, A., Robson, T., ... McKeown, S. (2008). Evaluation of the antiangiogenic potential of AQ4N. Clinical Cancer Research, 14(5), 1502-1509. https://doi.org/10.1158/1078-0432.CCR-07-1262
    O'Rourke, Martin ; Ward, Claire ; Worthington, Jenny ; McKenna, Julie ; Valentine, Andrea ; Robson, Tracy ; Hirst, David G ; McKeown, Stephanie. / Evaluation of the antiangiogenic potential of AQ4N. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 5. pp. 1502-1509.
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    title = "Evaluation of the antiangiogenic potential of AQ4N",
    abstract = "Purpose: A number of cytotoxic chemotherapy agents tested at low concentrations show antiangiogenic properties with limited cytotoxicity, e.g., cyclophosphamide, tirapazamine, and mitoxantrone. AQ4N is a bioreductive alkylaminoanthraquinone that is cytotoxic when reduced to AQ4; hence, it can be used to target hypoxic tumor cells. AQ4N is structurally similar to mitoxantrone and was evaluated for antiangiogenic properties without the need for bioreduction.@ Experimental Design: The effect of AQ4N and fumagillin on human microvascular endothelial cells (HMEC-1) was measured using a variety of in vitro assays, i.e., 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound scrape, tubule formation, rat aortic ring, and invasion assays. Low-doseAQ4N (20 mg/kg) was also given in vivo to mice bearing a tumor in a dorsal skin flap.@ Results: AQ4N (10(-11) to 10(-5) mol/L) had no effect on HMEC-1 viability. AQ4N (10(-9) to 10(-5) mol/L) caused a sigmoidal dose-dependent inhibition of endothelial cell migration in the wound scrape model. Fumagillin showed a similar response over a lower dose range (10(-13) to 10(-9) mol/L); however, the maximal inhibition was less (25{\%} versus 43{\%} for AQ4N). AQ4N inhibited HMEC-1 cell contacts on Matrigel (10(-8) to 10(-5) mol/L), HMEC-1 cell invasion, and sprouting in rat aorta explants. Immunofluorescence staining with tubulin, vimentim, dynein, and phalloidin revealed that AQ4N caused disruption to the cell cytoskeleton. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap.@ Conclusions: This combination of assays has shown that AQ4N possesses antiangiogenic effects in normoxic conditions, which could potentially contribute to antitumor activity.",
    author = "Martin O'Rourke and Claire Ward and Jenny Worthington and Julie McKenna and Andrea Valentine and Tracy Robson and Hirst, {David G} and Stephanie McKeown",
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    O'Rourke, M, Ward, C, Worthington, J, McKenna, J, Valentine, A, Robson, T, Hirst, DG & McKeown, S 2008, 'Evaluation of the antiangiogenic potential of AQ4N', Clinical Cancer Research, vol. 14, no. 5, pp. 1502-1509. https://doi.org/10.1158/1078-0432.CCR-07-1262

    Evaluation of the antiangiogenic potential of AQ4N. / O'Rourke, Martin; Ward, Claire; Worthington, Jenny; McKenna, Julie; Valentine, Andrea; Robson, Tracy; Hirst, David G; McKeown, Stephanie.

    In: Clinical Cancer Research, Vol. 14, No. 5, 03.2008, p. 1502-1509.

    Research output: Contribution to journalArticle

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    T1 - Evaluation of the antiangiogenic potential of AQ4N

    AU - O'Rourke, Martin

    AU - Ward, Claire

    AU - Worthington, Jenny

    AU - McKenna, Julie

    AU - Valentine, Andrea

    AU - Robson, Tracy

    AU - Hirst, David G

    AU - McKeown, Stephanie

    PY - 2008/3

    Y1 - 2008/3

    N2 - Purpose: A number of cytotoxic chemotherapy agents tested at low concentrations show antiangiogenic properties with limited cytotoxicity, e.g., cyclophosphamide, tirapazamine, and mitoxantrone. AQ4N is a bioreductive alkylaminoanthraquinone that is cytotoxic when reduced to AQ4; hence, it can be used to target hypoxic tumor cells. AQ4N is structurally similar to mitoxantrone and was evaluated for antiangiogenic properties without the need for bioreduction.@ Experimental Design: The effect of AQ4N and fumagillin on human microvascular endothelial cells (HMEC-1) was measured using a variety of in vitro assays, i.e., 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound scrape, tubule formation, rat aortic ring, and invasion assays. Low-doseAQ4N (20 mg/kg) was also given in vivo to mice bearing a tumor in a dorsal skin flap.@ Results: AQ4N (10(-11) to 10(-5) mol/L) had no effect on HMEC-1 viability. AQ4N (10(-9) to 10(-5) mol/L) caused a sigmoidal dose-dependent inhibition of endothelial cell migration in the wound scrape model. Fumagillin showed a similar response over a lower dose range (10(-13) to 10(-9) mol/L); however, the maximal inhibition was less (25% versus 43% for AQ4N). AQ4N inhibited HMEC-1 cell contacts on Matrigel (10(-8) to 10(-5) mol/L), HMEC-1 cell invasion, and sprouting in rat aorta explants. Immunofluorescence staining with tubulin, vimentim, dynein, and phalloidin revealed that AQ4N caused disruption to the cell cytoskeleton. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap.@ Conclusions: This combination of assays has shown that AQ4N possesses antiangiogenic effects in normoxic conditions, which could potentially contribute to antitumor activity.

    AB - Purpose: A number of cytotoxic chemotherapy agents tested at low concentrations show antiangiogenic properties with limited cytotoxicity, e.g., cyclophosphamide, tirapazamine, and mitoxantrone. AQ4N is a bioreductive alkylaminoanthraquinone that is cytotoxic when reduced to AQ4; hence, it can be used to target hypoxic tumor cells. AQ4N is structurally similar to mitoxantrone and was evaluated for antiangiogenic properties without the need for bioreduction.@ Experimental Design: The effect of AQ4N and fumagillin on human microvascular endothelial cells (HMEC-1) was measured using a variety of in vitro assays, i.e., 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound scrape, tubule formation, rat aortic ring, and invasion assays. Low-doseAQ4N (20 mg/kg) was also given in vivo to mice bearing a tumor in a dorsal skin flap.@ Results: AQ4N (10(-11) to 10(-5) mol/L) had no effect on HMEC-1 viability. AQ4N (10(-9) to 10(-5) mol/L) caused a sigmoidal dose-dependent inhibition of endothelial cell migration in the wound scrape model. Fumagillin showed a similar response over a lower dose range (10(-13) to 10(-9) mol/L); however, the maximal inhibition was less (25% versus 43% for AQ4N). AQ4N inhibited HMEC-1 cell contacts on Matrigel (10(-8) to 10(-5) mol/L), HMEC-1 cell invasion, and sprouting in rat aorta explants. Immunofluorescence staining with tubulin, vimentim, dynein, and phalloidin revealed that AQ4N caused disruption to the cell cytoskeleton. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap.@ Conclusions: This combination of assays has shown that AQ4N possesses antiangiogenic effects in normoxic conditions, which could potentially contribute to antitumor activity.

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    O'Rourke M, Ward C, Worthington J, McKenna J, Valentine A, Robson T et al. Evaluation of the antiangiogenic potential of AQ4N. Clinical Cancer Research. 2008 Mar;14(5):1502-1509. https://doi.org/10.1158/1078-0432.CCR-07-1262