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      1. Author :
        Lan, K. L.; Lan, K. H.; Sheu, M. L.; Chen, M. Y.; Shih, Y. S.; Hsu, F. C.; Wang, H. M.; Liu, R. S.; Yen, S. H.
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      3. Type :
        Journal Article
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      5. Publication :
        International journal of radiation biology
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      12. Abstract :
        PURPOSE: Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a pivotal role in the reaction of a tumour to hypoxia. In this study, we examined the inhibitory effect of a natural compound, honokiol, on HIF-1alpha activity and tumour growth in combination with radiation. METHODS: The inhibitory effect of honokiol on hypoxia-responsive element (HRE) controlled luciferase activity and HIF-1alpha accumulations stimulated by CoCl(2), or hypoxia was examined. Effect of honokiol on HIF-1alpha levels within hypoxic tumour microenvironment was investigated by immunohistochemical and in vivo bioluminescent studies. The in vivo radiosensitising activity of honokiol was evaluated with subcutaneous murine colon carcinoma, CT26, xenografts of BALB/c mice treated with honokiol, radiation, or both. RESULTS: Suppression of luciferase (luc) activity in HRE-luc stable cells by honokiol was in agreement with the results of decreased HIF-1alpha accumulation. In CT26-HRE-luc tumour-bearing mice, the inhibitory effect of intraperitoneally injected honokiol on HIF-1alpha-regulated luciferase activities induced by either CoCl(2) or radiation could be monitored non-invasively. Lastly, honokiol in combination with irradiation produced synergistic delay of CT26 tumour growth. CONCLUSIONS: Our data suggest that honokiol can exert its anticancer activity as a HIF-1alpha inhibitor by reducing HIF-1alpha protein level and suppressing the hypoxia-related signaling pathway. The animal experiment indicates that honokiol improves the therapeutic efficacy of radiation.
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