Honokiol inhibits hypoxia-inducible factor-1 pathway

Purpose: Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha activity and tumour growth in combination with radiation. Methods: The inhibitory effect of honokiol on hypoxia-responsive element (HRE) controlled luciferase activity and HIF-1 alpha accumulations stimulated by CoCl2, or hypoxia was examined. Effect of honokiol on HIF-1 alpha levels within hypoxic tumour microenvironment was investigated by immunohistochemical and in vivo bioluminescent studies. The in vivo radio-sensitising 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-1 alpha accumulation. In CT26-HRE-luc tumour-bearing mice, the inhibitory effect of intraperitoneally injected honokiol on HIF-1 alpha-regulated luciferase activities induced by either CoCl2 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-1 alpha inhibitor by reducing HIF-1 alpha protein level and suppressing the hypoxia-related signaling pathway. The animal experiment indicates that honokiol improves the therapeutic efficacy of radiation.