Myricetin treatment induces apoptosis in canine osteosarcoma cells by inducing DNA fragmentation, disrupting redox homeostasis, and mediating loss of mitochondrial membrane potential

J Cell Physiol. 2018 Sep;233(9):7457-7466. doi: 10.1002/jcp.26598. Epub 2018 Apr 16.

Abstract

Canine osteosarcoma is an aggressive primary bone tumor that shows metastasis to distal regions and is associated with a high mortality rate. However, the pathophysiological mechanisms of canine osteosarcoma are not well characterized. In addition, development of prognostic factors and novel therapeutic agents is necessary to efficiently treat osteosarcoma. Therefore, we studied the effects of myricetin, an antioxidant found in berries, nuts, teas, wine, and vegetables, on apoptosis and signal transduction in the canine osteosarcoma cell lines, D-17 and DSN. Results of the present study demonstrated that treatment with myricetin decreased cell proliferation and DNA replication, while it increased apoptotic DNA fragmentation in D-17 and DSN cells. In addition, it increased generation of ROS, lipid peroxidation, and depolarization of MMP in both D-17 and DSN cells. Myricetin treatment activated phosphorylation of AKT, p70S6K, ERK1/2, JNK, and p90RSK in canine osteosarcoma cells. Moreover, inhibition of PI3K and MAPK using LY294002, U0126, or SP600125, in addition to myricetin treatment, effectively suppressed cell proliferation compared to treatment with myricetin or each inhibitor alone. Therefore, we concluded that myricetin may be a potentially effective and less toxic therapeutic agent to prevent and control progression of canine osteosarcoma.

Keywords: apoptosis; cell signaling; myricetin; osteosarcoma; treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Fragmentation / drug effects*
  • Dogs
  • Flavonoids / pharmacology*
  • Homeostasis*
  • MAP Kinase Signaling System / drug effects
  • Membrane Potential, Mitochondrial / drug effects*
  • Models, Biological
  • Osteosarcoma / enzymology
  • Osteosarcoma / pathology*
  • Oxidation-Reduction
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Small Molecule Libraries / pharmacology

Substances

  • Flavonoids
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • myricetin
  • Phosphatidylinositol 3-Kinases