title: High concentrations of L-ascorbic acid specifically inhibit the growth of human leukemic cells via downregulation of HIF-1α transcription.
abstract: We examined the antileukemic effects of high concentrations of L-ascorbic acid (high AA) on human leukemic cells. In vitro, high AA markedly induced apoptosis in various leukemic cell lines by generating hydrogen peroxide (H2O2) but not in normal hematopoietic stem/progenitor cells. High AA significantly repressed leukemic cell proliferation as well as neoangiogenesis in immunodeficient mice. We then noted that in leukemic cells, HIF-1α transcription was strongly suppressed by high AA and correlated with the transcription of VEGF. Our data indicate that exposure to high AA markedly increased the intracellular AA content of leukemic cells and inhibited the nuclear translocation of NF-κB, which mediates expression of HIF-1α. We next generated K562 cells that overexpressed HIF-1α (K562-HIF1α cells) and assessed the mechanistic relationship between inhibition of HIF-1α transcription and the antileukemic effect of high AA. The ability of high AA to induce apoptosis was significantly lower in K562-HIF1α cells than in K562 cells in vitro. We found that expression of HIF-1α-regulated antiapoptotic proteins of the Bcl-2 family, such as Mcl-1, Bcl-xL, and Bcl-2, was significantly suppressed by high AA in K562 cells, but was sustained at higher levels in K562-HIF1α cells, regardless of high AA exposure. Moreover, repression of cell proliferation and neoangiogenesis by high AA was completely abrogated in mice receiving transplants of K562-HIF1α cells. These results indicate that, along with H2O2 generation, downregulation of HIF-1α transcription plays a crucial role in growth inhibition of human leukemic cells by high AA.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan. hkawada@is.icc.u-tokai.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawada
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Kaneko
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sawanobori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Uno
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Matsuzawa
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D001205:Ascorbic Acid / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D014158:Transcription, Genetic / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D001205:Ascorbic Acid