Honokiol inhibits hypoxia-inducible factor-1 pathway

Abstract

Purpose: Hypoxia-inducible factor-1α (HIF-1α) 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-1α activity and tumour growth in combination with radiation.

Methods: The inhibitory effect of honokiol on hypoxia-responsive element (HRE) controlled luciferase activity and HIF-1α accumulations stimulated by CoCl₂, or hypoxia was examined. Effect of honokiol on HIF-1α 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-1α accumulation. In CT26-HRE-luc tumour-bearing mice, the inhibitory effect of intraperitoneally injected honokiol on HIF-1α-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-1α inhibitor by reducing HIF-1α protein level and suppressing the hypoxia-related signaling pathway. The animal experiment indicates that honokiol improves the therapeutic efficacy of radiation.

Keywords:

• Hypoxia-inducible factor-1α (HIF-1α)
• hypoxia-responsive element (HRE)
• honokiol

Acknowledgements

This work was supported by grants from the National Science Council of Taiwan (NSC 96-2628-B-075-029-MY3) and the Taipei Veterans General Hospital (V96B1-003; V98C1-069). This work was assisted in part by the Division of Experimental Surgery of the Department of Surgery and Molecular and Genetic Imaging CoreMAGIC/NRPGM, Taipei Veterans General Hospital.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.