title: A novel synergistic effect of iron depletion on antiangiogenic cancer therapy.
abstract: Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion monotherapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The antitumor effects of iron depletion and antiangiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted antitumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohara
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Noma
authors.forename: Shinichi
authors.initials: S
authors.lastname: Urano
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Watanabe
authors.forename: Seishi
authors.initials: S
authors.lastname: Nishitani
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tomono
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Kimura
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shirakawa
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D000090463:Iron Deficiencies; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab