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Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines.
- Source :
-
PloS one [PLoS One] 2019 Sep 24; Vol. 14 (9), pp. e0222228. Date of Electronic Publication: 2019 Sep 24 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Antineoplastic Agents administration & dosage
Bone Neoplasms drug therapy
Cell Line, Tumor
Cyclophosphamide administration & dosage
Cyclophosphamide therapeutic use
Depsipeptides administration & dosage
Depsipeptides therapeutic use
Doxorubicin administration & dosage
Doxorubicin therapeutic use
Drug Synergism
Drug Therapy, Combination methods
Etoposide administration & dosage
Etoposide therapeutic use
Histone Deacetylase Inhibitors administration & dosage
Histone Deacetylases drug effects
Histone Deacetylases metabolism
Humans
Hydrazines administration & dosage
Hydrazines therapeutic use
Irinotecan administration & dosage
Irinotecan therapeutic use
Sarcoma, Ewing drug therapy
Sulfonamides administration & dosage
Sulfonamides therapeutic use
Vincristine administration & dosage
Vincristine therapeutic use
Antineoplastic Agents therapeutic use
Bone Neoplasms enzymology
Histone Deacetylase Inhibitors therapeutic use
Histone Demethylases antagonists & inhibitors
Sarcoma, Ewing enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 14
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 31550266
- Full Text :
- https://doi.org/10.1371/journal.pone.0222228