title: Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha.
abstract: Hypoxia-inducible factor-1alpha (HIF-1alpha) is an important transcriptional factor that is activated when mammalian cells experience hypoxia, a tumor microenvironmental condition that plays pivotal roles in tumor progression and treatment. In this study, we examined the idea of down-regulating HIF-1alpha in tumor cells for therapeutic gain. We show that the expression levels of HIF-1alpha can be significantly attenuated by use of the recently established small interfering RNA technology in combination with adenovirus-mediated gene transfer. Down-regulation of the HIF-1alpha protein enhanced hypoxia-mediated tumor cell apoptosis in vitro. Subcutaneous tumor growth was also prevented from cells with attenuated HIF-1alpha expression. In addition, intratumoral injection of adenovirus encoding the HIF-1alpha-targeted small interfering RNA had a small but significant effect on tumor growth when combined with ionizing radiation. Therefore, our results provide proof of HIF-1alpha as an effective target for anticancer therapy. They also suggest that an adenovirus-based small interfering RNA gene transfer approach may be a potentially effective adjuvant strategy for cancer treatment.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Xiuwu
authors.initials: X
authors.lastname: Zhang
authors.forename: Takashi
authors.initials: T
authors.lastname: Kon
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: John P
authors.initials: JP
authors.lastname: Kirkpatrick
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Chuan-Yuan
authors.initials: CY
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D011878:Radiotherapy; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D014157:Transcription Factors