title: PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells.
abstract: The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells. By itself, LB100 inhibited proliferation and induced significant apoptosis in a range of pediatric MB cell lines. It also attenuated MB cell migration, a pre-requirement for invasion. When used in combination, LB100 enhanced cisplatin-mediated cytotoxic effects. Cell viability in the presence of 1 uM cisplatin alone was 61% (DAOY), 100% (D341), and 58% (D283), but decreased with the addition of 2 μM of LB100 to 26% (DAOY), 67% (D341), and 27% (D283), (p < 0.005). LB100 suppressed phosphorylation of the STAT3 protein and several STAT3 downstream targets. Also, LB100 directly increased cisplatin uptake and overcame cisplatin-resistance in vitro. Finally, LB100 exhibited potent in vivo anti-neoplastic activity in combination with cisplatin in an intracranial xenograft model.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Winson S
authors.initials: WS
authors.lastname: Ho
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Feldman
authors.affiliation: NINDS Flow Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.affiliation: National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Amable
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.affiliation: Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993,USA.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Feldman
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Abhik
authors.initials: A
authors.lastname: Ray-Chaudhury
authors.affiliation: In Vivo NMR Center, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lizak
authors.affiliation: School of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Vera
authors.affiliation: Division of Neurosurgery, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
authors.forename: R Aaron
authors.initials: RA
authors.lastname: Robison
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Heiss
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C000708580:LB100; D010879:Piperazines; D054648:Protein Phosphatase 2; D002945:Cisplatin
keywords: LB100; PP2A; STAT3; cisplatin; medulloblastoma