title: Honokiol inhibits hypoxia-inducible factor-1 pathway.
abstract: OBJECTIVE
  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 CoCl(2), 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 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-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.
authors.affiliation: Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan. kllan@vghtpe.gov.tw
authors.forename: Keng-Li
authors.initials: KL
authors.lastname: Lan
authors.forename: Keng-Hsin
authors.initials: KH
authors.lastname: Lan
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Chen
authors.forename: Yi-Sheng
authors.initials: YS
authors.lastname: Shih
authors.forename: Fu-Chih
authors.initials: FC
authors.lastname: Hsu
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Wang
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.forename: Sang-Hue
authors.initials: SH
authors.lastname: Yen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry / Q000379:methods; D017705:Lignans / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D003035:Cobalt; D051793:Hypoxia-Inducible Factor 1; D017705:Lignans; D008156:Luciferases; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C018021:cobaltous chloride