PloS one, 2014-12, Vol.9 (12), p.e111840
2014
Details
- Autor(en) / Beteiligte
- Titel
- Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas
- Ist Teil von
- PloS one, 2014-12, Vol.9 (12), p.e111840
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- Electronic Journals Library - Freely accessible e-journals
- Beschreibungen/Notizen
- Patients with non-Hodgkin lymphoma (NHL) are treated today with a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Subsets of patients with NHL of germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical testing of the EZH2 inhibitor EPZ-6438 has recently begun in patients. We report here that combining EPZ-6438 with CHOP in preclinical cell culture and mouse models results in dramatic synergy for cell killing in EZH2 mutant germinal center NHL cells. Surprisingly, we observe that much of this synergy is due to Prednisolone - a glucocorticoid receptor agonist (GRag) component of CHOP. Dramatic synergy was observed when EPZ-6438 is combined with Prednisolone alone, and a similar effect was observed with Dexamethasone, another GRag. Remarkably, the anti-proliferative effect of the EPZ-6438+GRag combination extends beyond EZH2 mutant-bearing cells to more generally impact germinal center NHL. These preclinical data reveal an unanticipated biological intersection between GR-mediated gene regulation and EZH2-mediated chromatin remodeling. The data also suggest the possibility of a significant and practical benefit of combining EZH2 inhibitors and GRag that warrants further investigation in a clinical setting.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0111840Titel-ID: cdi_plos_journals_1635007356
- Format
- –
- Schlagworte
- Analysis, Animals, Anticancer properties, Antineoplastic Agents - pharmacology, Antineoplastic Combined Chemotherapy Protocols - pharmacology, Apoptosis, Benzamides - pharmacology, Biology and Life Sciences, Biphenyl Compounds, Cancer, Care and treatment, Cell growth, Cell Line, Tumor, Central nervous system depressants, Corticosteroids, Cyclophosphamide - pharmacology, Dexamethasone, Dexamethasone - pharmacology, Doxorubicin - pharmacology, Drug Evaluation, Preclinical, Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors, Enhancer of Zeste Homolog 2 Protein - metabolism, Enzymes, Female, Fluocinolone acetonide, Gene expression, Gene Expression Regulation, Neoplastic - drug effects, Germinal centers, Glucocorticoids, Glucocorticoids - pharmacology, Histones, Humans, Immunosuppressive agents, Inhibitors, Lymphoma, Lymphoma, Non-Hodgkin - drug therapy, Lymphoma, Non-Hodgkin - metabolism, Medicine and health sciences, Mice, SCID, Morpholines, Mutation, Neoplasm Transplantation, Non-Hodgkin's lymphomas, Prednisolone, Prednisolone - pharmacology, Prednisone - pharmacology, Pyridones - pharmacology, R&D, Random Allocation, Receptors, Glucocorticoid - agonists, Receptors, Glucocorticoid - metabolism, Research & development, Signal transduction, Steroids, Vincristine - pharmacology