title: Inhibition of protein phosphatase 2A with a small molecule LB100 radiosensitizes nasopharyngeal carcinoma xenografts by inducing mitotic catastrophe and blocking DNA damage repair.
abstract: Nasopharyngeal carcinoma (NPC), while uncommon worldwide, is a major health problem in China. Although local radiation and surgery provide good control of NPC, better treatments that permit reductions in radiation dosing are needed. Inhibition of protein phosphatase 2A (PP2A), a ubiquitous multifunctional enzyme with critical roles in cell cycle regulation and DNA-damage response, reportedly sensitizes cancer cells to radiation and chemotherapy. We studied PP2A inhibition with LB100, a small molecule currently in a Phase I clinical trial, on radiosensitization of two human nasopharyngeal cell lines: CNE1, which is reportedly radioresistant, and CNE2. In both cell lines, LB100 exposure increased intracellular p-Plk1, TCTP, and Cdk1 and decreased p53, changes associated with cell cycle arrest, mitotic catastrophe and radio-inhibition of cell proliferation. Mice bearing subcutaneous xenografts of either cell line were administered 1.5 mg/kg LB100 daily for three days and a single dose of 20 Gy radiation (day 3), which produced marked and prolonged tumor mass regression (dose enhancement factors of 2.98 and 2.27 for CNE1 and CNE2 xenografts, respectively). Treatment with either LB100 or radiation alone only transiently inhibited xenograft growth. Our results support further exploration of PP2A inhibition as part of radiotherapy regimens for NPC and potentially other solid tumors.
authors.affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS) ,Beijing , People's Republic of China. Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lv
authors.affiliation: Institute for Medical Device Standardization Administration, National Institutes for Food and Drug Control, Beijing , People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS) ,Beijing , People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS) ,Beijing , People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute for Medical Device Standardization Administration, National Institutes for Food and Drug Control, Beijing , People's Republic of China.
authors.forename: Jing-Li
authors.initials: JL
authors.lastname: Li
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD ,USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hong
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD ,USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS) ,Beijing , People's Republic of China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong , People's Republic of China. State Key Laboratory of Oncology in Southern China, Guangzhou, Guangdong , People's Republic of China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis / Q000187:drug effects*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000090324:Tumor Protein, Translationally-Controlled 1; D023041:Xenograft Model Antitumor Assays
chemical_list: D011838:Radiation-Sensitizing Agents; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2