Eltrombopag Inhibits the Proliferation of Ewing Sarcoma Cells Via Iron Chelation and Impaired DNA Replication

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2020 Dec 1

PMID 33256675

Citations 6

Authors

Torin Waters

Kelli L Goss

Stacia L Koppenhafer

William W Terry

David J Gordon

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Citing Articles

Auranofin and reactive oxygen species inhibit protein synthesis and regulate the level of the PLK1 protein in Ewing sarcoma cells.

Haight J, Koppenhafer S, Geary E, Gordon D Front Oncol. 2024; 14:1394653.

PMID: 38933441 PMC: 11199525. DOI: 10.3389/fonc.2024.1394653.

Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress.

Croushore E, Koppenhafer S, Goss K, Geary E, Gordon D Cancer Res Commun. 2023; 3(8):1580-1593.

PMID: 37599787 PMC: 10434289. DOI: 10.1158/2767-9764.CRC-23-0268.

Eltrombopag increases the hematopoietic supporting ability of mesenchymal stem/stromal cells.

Muntion S, Preciado S, Sanchez-Luis E, Corchete L, Diez-Campelo M, Osugui L Ther Adv Hematol. 2023; 13:20406207221142137.

PMID: 36601635 PMC: 9806379. DOI: 10.1177/20406207221142137.

Emerging Roles of the Iron Chelators in Inflammation.

Di Paola A, Tortora C, Argenziano M, Marrapodi M, Rossi F Int J Mol Sci. 2022; 23(14).

PMID: 35887336 PMC: 9318075. DOI: 10.3390/ijms23147977.

Inhibitor of DNA binding 2 (ID2) regulates the expression of developmental genes and tumorigenesis in ewing sarcoma.

Koppenhafer S, Goss K, Voigt E, Croushore E, Terry W, Ostergaard J Oncogene. 2022; 41(20):2873-2884.

PMID: 35422476 PMC: 9107507. DOI: 10.1038/s41388-022-02310-0.

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