Oncotarget

Research Papers:

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 and John D. Heiss _

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Oncotarget. 2016; 7:12447-12463. https://doi.org/10.18632/oncotarget.6970

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Abstract

Winson S. Ho1,*, Michael J. Feldman1,*, Dragan Maric2, Lauren Amable3, Matthew D. Hall4, Gerald M. Feldman5, Abhik Ray-Chaudhury1, Martin J. Lizak6, Juan-Carlos Vera7, R. Aaron Robison8, Zhengping Zhuang1, John D. Heiss1

1Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

2NINDS Flow Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

3National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892

4National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA

5Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993

6In Vivo NMR Center, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD 20892

7School of Medicine, Tulane University, New Orleans, LA 70112

8Division of Neurosurgery, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027

*These authors have contributed equally to this work

Correspondence to:

John D. Heiss, e-mail: [email protected]

Zhengping Zhuang, e-mail: [email protected]

Keywords: medulloblastoma, PP2A, LB100, STAT3, cisplatin

Received: September 14, 2015     Accepted: January 01, 2016     Published: January 21, 2016

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.


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