Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication

Torin Waters; Kelli L Goss; Stacia L Koppenhafer; William W Terry; David J Gordon

doi:10.1186/s12885-020-07668-6

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Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication

Journal article

Open access

Peer reviewed

Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication

Torin Waters, Kelli L Goss, Stacia L Koppenhafer, William W Terry and David J Gordon

BMC cancer, Vol.20(1), pp.1171-1171

11/30/2020

DOI: 10.1186/s12885-020-07668-6

PMCID: PMC7706234

PMID: 33256675

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Abstract

The treatment of Ewing sarcoma, an aggressive bone and soft tissue sarcoma, is associated with suboptimal outcomes and significant side-effects. Consequently, there is an urgent need to identify novel therapies that will improve outcomes for children and adults with Ewing sarcoma tumors while also decreasing treatment-related toxicities. We analyzed data from the PRISM drug repurposing screen, which tested the activity of 4518 drugs across 578 cancer cell lines, to identify drugs that selectively inhibit the growth of Ewing sarcoma cell lines. We then tested the effects of a top hit from the screen on cell proliferation, cell cycle progression, and activation of the DNA damage pathway using Ewing sarcoma cell lines. We also used a CRISPR/Cas9 gene knockout approach to investigate the role of Schlafen 11 (SLFN11), a restriction factor for DNA replication stress that is overexpressed in Ewing sarcoma tumors, in mediating the sensitivity of Ewing sarcoma cells to the drug. We found that eltrombopag, an FDA-approved thrombopoietin-receptor agonist (TPO-RA) that is currently being evaluated as a treatment for chemotherapy-induced thrombocytopenia, inhibits the growth of Ewing sarcoma cell lines in vitro in proliferation and colony formation assays. However, from a mechanistic standpoint, the thrombopoietin receptor is not expressed in Ewing sarcoma cells and we show that eltrombopag impairs DNA replication and causes DNA damage in Ewing sarcoma cells by chelating iron, a known "off-target" effect of the drug. We also found that the sensitivity of Ewing sarcoma cells to eltrombopag is mediated, in part, by SLFN11, which regulates the cellular response to DNA replication stress. Ewing sarcoma cell lines are sensitive to eltrombopag and this drug could improve outcomes for patients with Ewing sarcoma tumors by both targeting the tumor, via chelation of iron and inhibition of DNA replication, and reducing chemotherapy-induced thrombocytopenia, via stimulation of the thrombopoietin receptor.

Benzoates - pharmacology

Benzoates - therapeutic use

Cell Proliferation

DNA Replication - genetics

Humans

Hydrazines - pharmacology

Hydrazines - therapeutic use

Iron Chelating Agents - pharmacology

Iron Chelating Agents - therapeutic use

Pyrazoles - pharmacology

Pyrazoles - therapeutic use

Sarcoma, Ewing - drug therapy

Details

Title: Subtitle: Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication
Creators: Torin Waters - University of Iowa
Kelli L Goss - University of Iowa
Stacia L Koppenhafer - University of Iowa
William W Terry - University of Iowa
David J Gordon - University of Iowa
Resource Type: Journal article
Publication Details: BMC cancer, Vol.20(1), pp.1171-1171
DOI: 10.1186/s12885-020-07668-6
PMID: 33256675
PMCID: PMC7706234
NLM abbreviation: BMC Cancer
ISSN: 1471-2407
eISSN: 1471-2407
Grant note: R37-CA217910 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R37 CA217910 / NCI NIH HHS
Language: English
Date published: 11/30/2020
Academic Unit: Stead Family Department of Pediatrics; Hematology/Oncology
Record Identifier: 9984354042102771

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