title: Metformin displaysin vitroandin vivoantitumor effect against osteosarcoma.
abstract: OBJECTIVE
  Patients with unresectable, relapsed, or refractory osteosarcoma need a novel therapeutic agent. Metformin is a biguanide derivative used in the treatment of type II diabetes, and is recently gaining attention in cancer research.
  
  
  METHODS
  We evaluated the effect of metformin against human osteosarcoma. Four osteosarcoma cell lines (KHOS/NP, HOS, MG-63, U-2 OS) were treated with metformin and cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were evaluated using flow cytometric analysis, and migration and wound healing assay were performed. Fourteen female Balb/c-nude mice received KHOS/NP cell grafts in their thigh, and were allowed access to metformin containing water (2 mg/mL)ad libitum. Tumor volume was measured every 3-4 days for a period of 4 weeks.
  
  
  RESULTS
  Metformin had a significant antiproliferative effect on human osteosarcoma cells. In particular, metformin inhibited the proliferation and migration of KHOS/NP cells by activation of AMP-activated protein kinase and consequent inhibition of the mammalian target of rapamycin pathway. It also inhibited the proliferation of cisplatin-resistant KHOS/NP clone cells. Analysis of KHOS/NP xenograft Balb/c-nude models indicated that metformin displayed potentin vivoantitumor effects.
  
  
  CONCLUSIONS
  Further studies are necessary to explore metformin's therapeutic potential and the possibilities for its use as an adjuvant agent for osteosarcoma.
authors.affiliation: Division of Clinical Translational Research, Korea Cancer Center Hospital, Seoul, Korea.
authors.forename: Yunmi
authors.initials: Y
authors.lastname: Ko
authors.affiliation: Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea.
authors.forename: Aery
authors.initials: A
authors.lastname: Choi
authors.affiliation: Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Division of Clinical Translational Research, Korea Cancer Center Hospital, Seoul, Korea.; Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea.
authors.forename: Jun Ah
authors.initials: JA
authors.lastname: Lee
keywords: Antitumor effect; Metformin; Osteosarcoma