PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells

Winson S Ho; Michael J Feldman; Dragan Maric; Lauren Amable; Matthew D Hall; Gerald M Feldman; Abhik Ray-Chaudhury; Martin J Lizak; Juan-Carlos Vera; R Aaron Robison; Zhengping Zhuang; John D Heiss

doi:10.18632/oncotarget.6970

PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells

Oncotarget. 2016 Mar 15;7(11):12447-63. doi: 10.18632/oncotarget.6970.

Authors

Affiliations

¹ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
² NINDS Flow Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
³ National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
⁵ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993,USA.
⁶ In Vivo NMR Center, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ School of Medicine, Tulane University, New Orleans, LA 70112, USA.
⁸ Division of Neurosurgery, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.

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.

Keywords: LB100; PP2A; STAT3; cisplatin; medulloblastoma.

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Cell Line, Tumor
Cerebellar Neoplasms / drug therapy*
Cerebellar Neoplasms / enzymology
Cerebellar Neoplasms / pathology
Cisplatin / administration & dosage
Cisplatin / pharmacology*
Drug Resistance, Neoplasm
Drug Synergism
Humans
Medulloblastoma / drug therapy*
Medulloblastoma / enzymology
Medulloblastoma / pathology
Mice
Mice, SCID
Piperazines / administration & dosage
Piperazines / pharmacology*
Protein Phosphatase 2 / antagonists & inhibitors*
Protein Phosphatase 2 / metabolism
Xenograft Model Antitumor Assays

Substances

Bridged Bicyclo Compounds, Heterocyclic
LB100
Piperazines
Protein Phosphatase 2
Cisplatin