机构:[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重点科室诊疗科室神经外科神经外科首都医科大学附属天坛医院[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
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 gamma-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 G(2)/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.
基金:
Intramural Research Program, CCR, NCI, National Institutes of Health
第一作者机构:[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
通讯作者:
通讯机构:[1]Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA[*1]Neuro-Oncology Branch, NCI, NIH, 9030 Old Georgetown Rd, Bethesda, MD 20892
推荐引用方式(GB/T 7714):
Shuyu Hao,Hua Song,Wei Zhang,et al.Protein phosphatase 2A inhibition enhances radiation sensitivity and reduces tumor growth in chordoma[J].NEURO-ONCOLOGY.2018,20(6):799-809.doi:10.1093/neuonc/nox241.
APA:
Shuyu Hao,Hua Song,Wei Zhang,Ashlee Seldomridge,Jinkyu Jung...&Deric M. Park.(2018).Protein phosphatase 2A inhibition enhances radiation sensitivity and reduces tumor growth in chordoma.NEURO-ONCOLOGY,20,(6)
MLA:
Shuyu Hao,et al."Protein phosphatase 2A inhibition enhances radiation sensitivity and reduces tumor growth in chordoma".NEURO-ONCOLOGY 20..6(2018):799-809