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

被引：30

作者：

Ho, Winson S. ^{[1
]}

Feldman, Michael J. ^{[1
]}

Maric, Dragan ^{[2
]}

Amable, Lauren ^{[3
]}

Hall, Matthew D. ^{[4
]}

Feldman, Gerald M. ^{[5
]}

Ray-Chaudhury, Abhik ^{[1
]}

Lizak, Martin J. ^{[6
]}

Vera, Juan-Carlos ^{[7
]}

Robison, R. Aaron ^{[8
]}

Zhuang, Zhengping ^{[1
]}

Heiss, John D. ^{[1
]}

机构：

[1] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA

[2] NINDS, NINDS Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA

[3] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA

[4] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA

[5] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[6] NINDS, In Vivo NMR Ctr, NIH, Bethesda, MD 20892 USA

[7] Tulane Univ, Sch Med, New Orleans, LA 70112 USA

[8] Univ So Calif, Childrens Hosp Los Angeles, Div Neurosurg, Los Angeles, CA 90027 USA

来源：

ONCOTARGET | 2016年 / 7卷 / 11期

基金：

美国国家卫生研究院;

关键词：

medulloblastoma; PP2A; LB100; STAT3; cisplatin; PROTEIN PHOSPHATASE 2A; MITOTIC CATASTROPHE; GROWTH ARREST; BRAIN-TUMORS; STAT3; CANCER; PHOSPHORYLATION; TARGET; CHEMOTHERAPY; CARBOPLATIN;

D O I：

10.18632/oncotarget.6970

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 mu M 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.

引用

页码：12447 / 12463

页数：17

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