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Neuro Oncol. 2018 May 18;20(6):799-809. doi: 10.1093/neuonc/nox241.

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

Author information

1
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
2
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
3
Flow Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
4
Ultrastructural Pathology Section, National Eye Institute, Bethesda, Maryland, USA.
5
Neuropathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
6
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

Abstract

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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.

PMID:
29294092
PMCID:
PMC5961117
[Available on 2019-05-18]
DOI:
10.1093/neuonc/nox241
[Indexed for MEDLINE]

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