title: Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy.
abstract: Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tumour radioresistance; therefore, it is recognised as an excellent target during radiation therapy. However, the inhibition of HIF-1 in unsuitable timing can suppress rather than enhance the effect of radiation therapy because its anti-angiogenic effect increases the radioresistant hypoxic fraction. In this study, we imaged changes of HIF-1 activity after treatment with radiation and/or an HIF-1 inhibitor, YC-1, and optimised their combination. Hypoxic tumour cells were reoxygenated 6 h postirradiation, leading to von Hippel-Lindau (VHL)-dependent proteolysis of HIF-1alpha and a resultant decrease in HIF-1 activity. The activity then increased as HIF-1alpha accumulated in the reoxygenated regions 24 h postirradiation. Meanwhile, YC-1 temporarily but significantly suppressed HIF-1 activity, leading to a decrease in microvessel density and an increase in tumour hypoxia. On treatment with YC-1 and then radiation, the YC-1-mediated increase in tumour hypoxia suppressed the effect of radiation therapy, whereas on treatment in the reverse order, YC-1 suppressed the postirradiation upregulation of HIF-1 activity and consequently delayed tumour growth. These results indicate that treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the therapeutic effect of radiation, and the suppression of the postirradiation upregulation of HIF-1 activity is important for the best therapeutic benefit.
authors.affiliation: Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Japan. hharada@kuhp.kyoto-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: S
authors.initials: S
authors.lastname: Itasaka
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: L
authors.initials: L
authors.lastname: Zeng
authors.forename: X
authors.initials: X
authors.lastname: Xie
authors.forename: A
authors.initials: A
authors.lastname: Morinibu
authors.forename: K
authors.initials: K
authors.lastname: Shinomiya
authors.forename: M
authors.initials: M
authors.lastname: Hiraoka
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D010101:Oxygen Consumption / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*; D011837:Radiation-Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D005663:Furans; D051793:Hypoxia-Inducible Factor 1; D007191:Indazoles; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole