Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines


Autoři: Darcy Welch aff001;  Elliot Kahen aff001;  Brooke Fridley aff003;  Andrew S. Brohl aff004;  Christopher L. Cubitt aff002;  Damon R. Reed aff001
Působiště autorů: Sunshine Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America aff001;  Translational Research Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America aff002;  Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America aff003;  Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America aff004;  Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America aff005;  Adolescent and Young Adult Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222228

Souhrn

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.

Klíčová slova:

Cell viability testing – Cyclophosphamide – Drug metabolism – Drug therapy – Chemotherapeutic agents – Chemotherapy – Ewing sarcoma – Synergy testing


Zdroje

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