title: Development of Stemness in Cancer Cell Lines Resistant to the Anticancer Effects of Zoledronic Acid.
abstract: BACKGROUND
  Drug resistance is closely related to cancer cell stemness, that is acquired along with resistance to various anticancer agents. However, this has not been investigated as a potential mechanism underlying cancer cell resistance to zoledronate, that is used to suppress bone metastasis.
  
  
  METHODS
  Zoledronate-resistant A549 lung cancer and MG63 osteosarcoma cell lines were established by repeated treatment with sub-lethal concentrations of zoledronate. Expression levels of the stem cell marker NANOG, cMYC, octamer-binding transcription factor 4, and sex-determining region Y-box 2 were evaluated and sphere formation was compared between parental and resistant cell lines. Tumourigenicity was assessed in vivo.
  
  
  RESULTS
  Stem cell marker expression was up-regulated and sphere formation was enhanced in resistant compared to parental cells and showed greater tumour formation capacity in mice.
  
  
  CONCLUSIONS
  Repeated treatment of malignant tumour cell lines with zoledronate, induces the development of drug resistance and stemness.
authors: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
authors: Akira
authors: A
authors: Yoshiyama
authors: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan t-morii@gb3.so-net.ne.jp.
authors: Takeshi
authors: T
authors: Morii
authors: Department of Clinical Laboratory Medicine, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
authors: Kouki
authors: K
authors: Ohtsuka
authors: Department of Clinical Laboratory Medicine, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
authors: Hiroaki
authors: H
authors: Ohnishi
authors: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan Department of Drug Design Proteome Area of Research, National Cancer Research Center Research Institute, Tsukiji, Chuuo-ku, Tokyo, Japan.
authors: Takashi
authors: T
authors: Tajima
authors: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
authors: Takayuki
authors: T
authors: Aoyagi
authors: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
authors: Kazuo
authors: K
authors: Mochizuki
authors: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
authors: Kazuhiko
authors: K
authors: Satomi
authors: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
authors: Shoichi
authors: S
authors: Ichimura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D014408:Biomarkers, Tumor; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Osteosarcoma; cancer stem cells; drug resistance; lung cancer; zoledronic acid