title: 5-Aminolevulinic Acid-Based Sonodynamic Therapy Induces the Apoptosis of Osteosarcoma in Mice.
abstract: OBJECTIVE
  Sonodynamic therapy (SDT) is promising for treatment of cancer, but its effect on osteosarcoma is unclear. This study examined the effect of 5-Aminolevulinic Acid (5-ALA)-based SDT on the growth of implanted osteosarcoma and their potential mechanisms in vivo and in vitro.
  
  
  METHODS
  The dose and metabolism of 5-ALA and ultrasound periods were optimized in a mouse model of induced osteosarcoma and in UMR-106 cells. The effects of ALA-SDT on the proliferation and apoptosis of UMR-106 cells and the growth of implanted osteosarcoma were examined. The levels of mitochondrial membrane potential (ΔψM), ROS production, BcL-2, Bax, p53 and caspase 3 expression in UMR-106 cells were determined.
  
  
  RESULTS
  Treatment with 5-ALA for eight hours was optimal for ALA-SDT in the mouse tumor model and treatment with 2 mM 5-ALA for 6 hours and ultrasound (1.0 MHz 2.0 W/cm2) for 7 min were optimal for UMR-106 cells. SDT, but not 5-ALA, alone inhibited the growth of implanted osteosarcoma in mice (P<0.01) and reduced the viability of UMR-106 cells (p<0.05). ALA-SDT further reduced the tumor volumes and viability of UMR-106 cells (p<0.01 for both). Pre-treatment with 5-ALA significantly enhanced the SDT-mediated apoptosis (p<0.01) and morphological changes. Furthermore, ALA-SDT significantly reduced the levels of ΔψM, but increased levels of ROS in UMR-106 cells (p<0.05 or p<0.01 vs. the Control or the Ultrasound). Moreover, ALA-SDT inhibited the proliferation of osteosarcoma cells and BcL-2 expression, but increased levels of Bax, p53 and caspase 3 expression in the implanted osteosarcoma tissues (p<0.05 or p<0.01 vs. the Control or the Ultrasound).
  
  
  CONCLUSIONS
  The ALA-SDT significantly inhibited osteosarcoma growth in vivo and reduced UMR-106 cell survival by inducing osteosarcoma cell apoptosis through the ROS-related mitochondrial pathway.
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Yongning
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Photo- and Sono-theranostic Technologies and Condensed Matter Science and Technology Institute, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Laboratory of Photo- and Sono-theranostic Technologies and Condensed Matter Science and Technology Institute, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Laboratory of Photo- and Sono-theranostic Technologies and Condensed Matter Science and Technology Institute, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Cardiovascular Institute, the First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Anatomy, College of Basic Medical Sciences, Harbin Medical University, Harbin, 150080, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anatomy, College of Basic Medical Sciences, Harbin Medical University, Harbin, 150080, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zheng
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China; Materials Research Institute, the Pennsylvania State University, University Park, PA, 16802, United States of America.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Cao
mesh_terms: D000622:Aminolevulinic Acid / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D012516:Osteosarcoma / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013010:Sonication; D014464:Ultrasonic Therapy; D014463:Ultrasonography
chemical_list: D017382:Reactive Oxygen Species; D000622:Aminolevulinic Acid