1,2:5,6-dianhydrogalactitol inhibits human glioma cell growth in vivo and in vitro by arresting the cell cycle at G 2/M phase

Acta Pharmacol Sin. 2017 Apr;38(4):561-570. doi: 10.1038/aps.2016.154. Epub 2017 Feb 20.

Abstract

1,2:5,6-dianhydrogalactitol (DAG) is a hexitol epoxide with marked antitumor activity against multiple types of cancer cells, but the molecular mechanisms by which DAG functions as an antitumor agent is largely unknown. In this study, we investigated the inhibitory effects of DAG on human glioma cell growth in vitro and in vivo and uncovered the underlying molecular mechanisms. Treatment with DAG (120 μmol/L) dose-dependently inhibited the proliferation and colony formation in human glioma cell lines LN229, U251, and U87MG in vitro. DAG (1, 2, 5 μmol/L) induced cell cycle arrest at G2/M phase in the 3 glioma cell lines in a dose-dependent manner. The signaling pathways involved in DAG-caused cell cycle arrest was further analyzed in LN229 cells, which revealed that DAG dose-dependently activated two parallel signaling cascades, ie, the p53-p21 cascade and the CDC25C-CDK1 cascade. DAG also significantly enhanced the radiosensitivity of LN229 cells as shown in the clonogenic assay. In nude mice bearing subcutaneously xenografted LN229 glioma, administration of DAG (5 mg/kg, iv, twice per week for 6 weeks) effectively suppressed the growth of xenografted tumors: the relative tumor growth rate (T/C) was reduced to 22.38%, and the tumor growth inhibitory rate (TGI) was 83.58% (P<0.01). In addition, DAG administration significantly activated the CDC25C-CDK1 cascade in the xenografted tumors. In conclusion, DAG inhibited human glioma cell growth in vitro and in vivo by inducing cell cycle arrest at G2/M phase. Two parallel cascades are activated and involved in the cell cycle arrest.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • CDC2 Protein Kinase
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinases / metabolism
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • Glioma / drug therapy*
  • Glioma / pathology
  • Heterografts
  • Humans
  • Mice, Nude
  • Neoplasm Transplantation
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism
  • cdc25 Phosphatases / metabolism

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • CDC25C protein, human
  • cdc25 Phosphatases