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    Apoptosis induction of poly-S-nitrosated human serum albumin in resistant solid tumor under hypoxia can be restored by phosphodiesterase 5 inhibition

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    Authors
    Ikeda, M.
    Ishima, Y.
    Chuang, Victor
    Ikeda, T.
    Kinoshita, R.
    Watanabe, H.
    Ishida, T.
    Otagiri, M.
    Maruyama, T.
    Date
    2016
    Type
    Journal Article
    
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    Citation
    Ikeda, M. and Ishima, Y. and Chuang, V. and Ikeda, T. and Kinoshita, R. and Watanabe, H. and Ishida, T. et al. 2016. Apoptosis induction of poly-S-nitrosated human serum albumin in resistant solid tumor under hypoxia can be restored by phosphodiesterase 5 inhibition. Nitric Oxide: Biology and Chemistry. 69: pp. 28-34.
    Source Title
    Nitric Oxide: Biology and Chemistry
    DOI
    10.1016/j.niox.2017.04.005
    ISSN
    1089-8603
    School
    School of Pharmacy
    URI
    http://hdl.handle.net/20.500.11937/53941
    Collection
    • Curtin Research Publications
    Abstract

    Poly-S-nitrosated human serum albumin (Poly-SNO-HSA) delivered and accumulated nitric oxide (NO) in tumors and induces apoptosis. Tumor hypoxia is strongly associated with malignant progression and tumor resistance to therapy. In this study, we examined the cytotoxic effect of Poly-SNO-HSA under hypoxia on the murine colon 26 adenocarcinoma (C26) cells in vitro and in vivo. Under hypoxia, at about 4 times LD50 dose of Poly-SNO-HSA in vitro, the reactive oxygen species production was hindered but apoptotic cells were induced via cGMP pathway as the effect was suppressed by a soluble guanylate cyclase inhibitor, NS2028. The apoptosis induction effect of low dose Poly-SNO-HSA on C26 cells in vitro under hypoxia can be restored by a phosphodiesterase 5 (PDE5) inhibitor, vardenafil. In C26-bearing mice, Poly-SNO-HSA/vardenafil combination treatment significantly suppressed the tumor volume compared with Poly-SNO-HSA or vardenafil treatment alone. Furthermore, the core tumor tissues showed increased expression of caspase-3 than the non-core tissue. The expression of caspase-3 appeared to overlap with the hypoxic zone of tumor tissues. Similar results were also obtained when the experiments were repeated using Epimedium extract, a natural herbal supplement with PDE5 inhibition activity. In conclusion, Poly-SNO-HSA/PDE5 inhibitors combination therapy is a promising approach for enhancing the anticancer therapeutic effects of Poly-SNO-HSA against not only anti-cancer drug resistance but also hypoxic stress related solid tumor resistance.

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