High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-Fli1 inhibition

Ola Awad, Jason T. Yustein, Preeti Shah, Naheed Gul, Varalakshmi Katuri, Alison O'Neill, Yali Kong, Milton L. Brown, Jeffrey A. Toretsky, David M. Loeb

Research output: Contribution to journalArticle

Abstract

Background: Cancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing's sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model - remission is easily achieved, even for patients with metastatic disease, but relapse remains frequent and is usually fatal. Methodology/Principal Findings: We have isolated a subpopulation of Ewing's sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDHhigh) activity and are enriched for clonogenicity, sphere-formation, and tumor initiation. The ALDHhigh cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing's sarcoma cells both in vitro and in vivo. Conclusions/Significance: Ewing's sarcoma contains an ALDHhigh stem-like population of chemotherapy-resistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.

Original languageEnglish (US)
Article numbere13943
JournalPLoS One
Volume5
Issue number11
DOIs
StatePublished - 2010

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Ewing's Sarcoma
Chemotherapy
sarcoma
Stem cells
drug therapy
stem cells
Stem Cells
Tumors
Drug Therapy
Neoplastic Stem Cells
relapse
Cells
neoplasms
cells
Aldehyde Dehydrogenase
Poisons
Oncogene Proteins
aldehyde dehydrogenase
Recurrence
Verapamil

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-Fli1 inhibition. / Awad, Ola; Yustein, Jason T.; Shah, Preeti; Gul, Naheed; Katuri, Varalakshmi; O'Neill, Alison; Kong, Yali; Brown, Milton L.; Toretsky, Jeffrey A.; Loeb, David M.

In: PLoS One, Vol. 5, No. 11, e13943, 2010.

Research output: Contribution to journalArticle

Awad, O, Yustein, JT, Shah, P, Gul, N, Katuri, V, O'Neill, A, Kong, Y, Brown, ML, Toretsky, JA & Loeb, DM 2010, 'High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-Fli1 inhibition', PLoS One, vol. 5, no. 11, e13943. https://doi.org/10.1371/journal.pone.0013943
Awad, Ola ; Yustein, Jason T. ; Shah, Preeti ; Gul, Naheed ; Katuri, Varalakshmi ; O'Neill, Alison ; Kong, Yali ; Brown, Milton L. ; Toretsky, Jeffrey A. ; Loeb, David M. / High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-Fli1 inhibition. In: PLoS One. 2010 ; Vol. 5, No. 11.
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