Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma.
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.
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Ira K
IK
Gordon
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892.
Jie
J
Lu
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Christian A
CA
Graves
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Kristin
K
Huntoon
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Jason M
JM
Frerich
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Ryan H
RH
Hanson
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Xiaoping
X
Wang
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Christopher S
CS
Hong
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Winson
W
Ho
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Michael J
MJ
Feldman
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Barbara
B
Ikejiri
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Kheem
K
Bisht
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892.
Xiaoyuan S
XS
Chen
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Anita
A
Tandle
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Chunzhang
C
Yang
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
W Tristram
WT
Arscott
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892.
Donald
D
Ye
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
John D
JD
Heiss
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Russell R
RR
Lonser
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Kevin
K
Camphausen
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Zhengping
Z
Zhuang
D000818:Animals; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects* / Q000528:radiation effects; D010879:Piperazines / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D019086:Bridged Bicyclo Compounds, Heterocyclic; C468783:H2AX protein, human; D006657:Histones; C000708580:LB100; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D054648:Protein Phosphatase 2