Protein phosphatase 2A inhibition enhances radiation sensitivity and reduces tumor growth in chordoma

Standard therapy for chordoma consists of surgical resection followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in signal transduction, cell cycle progression, cell differentiation, and DNA repair. LB100 is a small-molec...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2018-05, Vol.20 (6), p.799-809
Main Authors: Hao, Shuyu, Song, Hua, Zhang, Wei, Seldomridge, Ashlee, Jung, Jinkyu, Giles, Amber J, Hutchinson, Marsha-Kay, Cao, Xiaoyu, Colwell, Nicole, Lita, Adrian, Larion, Mioara, Maric, Dragan, Abu-Asab, Mones, Quezado, Martha, Kramp, Tamalee, Camphausen, Kevin, Zhuang, Zhengping, Gilbert, Mark R, Park, Deric M
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Basic and Translational Investigations
Biomarkers, Tumor - metabolism
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Cell Movement
Cell Proliferation
Chordoma - drug therapy
Chordoma - enzymology
Chordoma - pathology
Female
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Invasiveness
Piperazines - pharmacology
Protein Phosphatase 2 - antagonists & inhibitors
Radiation Tolerance - drug effects
Signal Transduction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Summary:Standard therapy for chordoma consists of surgical resection followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in signal transduction, cell cycle progression, cell differentiation, and DNA repair. LB100 is a small-molecule inhibitor of PP2A designed to sensitize cancer cells to DNA damage from irradiation and chemotherapy. A recently completed phase I trial of LB100 in solid tumors demonstrated its safety. Here, we show the therapeutic potential of LB100 in chordoma. Three patient-derived chordoma cell lines were used: U-CH1, JHC7, and UM-Chor1. Cell proliferation was determined with LB100 alone and in combination with irradiation. Cell cycle progression was assessed by flow cytometry. Quantitative γ-H2AX immunofluorescence and immunoblot evaluated the effect of LB100 on radiation-induced DNA damage. Ultrastructural evidence for nuclear damage was investigated using Raman imaging and transmission electron microscopy. A xenograft model was established to determine potential clinical utility of adding LB100 to irradiation. PP2A inhibition in concert with irradiation demonstrated in vitro growth inhibition. The combination of LB100 and radiation also induced accumulation at the G2/M phase of the cell cycle, the stage most sensitive to radiation-induced damage. LB100 enhanced radiation-induced DNA double-strand breaks. Animals implanted with chordoma cells and treated with the combination of LB100 and radiation demonstrated tumor growth delay. Combining LB100 and radiation enhanced DNA damage-induced cell death and delayed tumor growth in an animal model of chordoma. PP2A inhibition by LB100 treatment may improve the effectiveness of radiation therapy for chordoma.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/nox241