title: Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-D-ribose.
abstract: An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity partially prevented hypoxia-induced apoptosis. 2-Deoxy-D-ribose inhibits a number of components of the caspase-mediated hypoxia-induced apoptotic pathway. It inhibits hypoxia-induced caspase 3 activation, mitochondrial cytochrome c release, downregulation of Bcl-2 and Bcl-x(L), upregulation of hypoxia-inducible factor (HIF)-1 alpha, and loss of mitochondrial transmembrane potential in human leukemia HL-60 cell line. These findings suggest a molecular mechanism by which 2-deoxy-d-ribose confers the resistance to apoptosis. Thus 2-deoxy-D-ribose-modulated suppression of HIF-1 alpha expression could prevent the hypoxia-induced decrease of the anti-apoptotic Bcl-2 and Bcl-x(L) on the mitochondria. 2-Deoxy-L-ribose and its analogs may enhance apoptosis and suppress the growth of tumors by competitively inhibiting the activities of 2-deoxy-d-ribose and thus these analogs show promise for anti-tumor therapy.
authors.affiliation: Department of Cancer Chemotherapy, Institute for Cancer Research, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Kitazono
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okumura
authors.forename: Ayako
authors.initials: A
authors.lastname: Tani
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sumizawa
authors.forename: Misako
authors.initials: M
authors.lastname: Haraguchi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Komatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchimiya
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Ren
authors.forename: Toshiro
authors.initials: T
authors.lastname: Motoya
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D003574:Cytochrome c Group / Q000378:metabolism; D003855:Deoxyribose / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D025801:Ubiquitin; D051020:bcl-X Protein; D003855:Deoxyribose; D013939:Thymidine Phosphorylase; D020169:Caspases