title: HIF-dependent antitumorigenic effect of antioxidants in vivo.
abstract: The antitumorigenic activity of antioxidants has been presumed to arise from their ability to squelch DNA damage and genomic instability mediated by reactive oxygen species (ROS). Here, we report that antioxidants inhibited three tumorigenic models in vivo. Inhibition of a MYC-dependent human B lymphoma model was unassociated with genomic instability but was linked to diminished hypoxia-inducible factor (HIF)-1 levels in a prolyl hydroxylase 2 and von Hippel-Lindau protein-dependent manner. Ectopic expression of an oxygen-independent, stabilized HIF-1 mutant rescued lymphoma xenografts from inhibition by two antioxidants: N-acetylcysteine and vitamin C. These findings challenge the paradigm that antioxidants diminish tumorigenesis primarily through decreasing DNA damage and mutations and provide significant support for a key antitumorigenic effect of diminishing HIF levels.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Ramani
authors.initials: R
authors.lastname: Dinavahi
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.forename: Linzhao
authors.initials: L
authors.lastname: Cheng
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pevsner
authors.forename: Linda A
authors.initials: LA
authors.lastname: Lee
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002460:Cell Line; D042822:Genomic Instability; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation