Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma

Mol Cancer Ther. 2015 Jul;14(7):1540-1547. doi: 10.1158/1535-7163.MCT-14-0614. Epub 2015 May 4.

Abstract

Protein phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiotherapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiotherapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of postradiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiotherapy maintained increased γ-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared with radiotherapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA-damage response pathway activity.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Blotting, Western
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Division / drug effects
  • Cell Division / radiation effects
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / radiotherapy
  • Histones / metabolism
  • Humans
  • Immunohistochemistry
  • Mice, Nude
  • Mitosis / drug effects*
  • Mitosis / radiation effects
  • Piperazines / pharmacology*
  • Protein Phosphatase 2 / antagonists & inhibitors*
  • Protein Phosphatase 2 / metabolism
  • Radiation Tolerance / drug effects
  • Radiation Tolerance / radiation effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Tumor Burden / drug effects*
  • Tumor Burden / radiation effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • H2AX protein, human
  • Histones
  • LB-100
  • Piperazines
  • Tumor Suppressor Protein p53
  • Protein Phosphatase 2