title: Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins.
abstract: Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors. Cancer Res; 76(8); 2376-83. ©2016 AACR.
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Nilsson
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lydia C
authors.initials: LC
authors.lastname: Green
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Somsundar Veppil
authors.initials: SV
authors.lastname: Muralidharan
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Dağsu
authors.initials: D
authors.lastname: Demir
authors.affiliation: SARomics Biostructures AB, Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Welin
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Bhadury
authors.affiliation: SARomics Biostructures AB, Lund, Sweden.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Logan
authors.affiliation: SARomics Biostructures AB, Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Walse
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center at University of Gothenburg, Gothenburg, Sweden. jonas.a.nilsson@surgery.gu.se.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D017346:Protein Serine-Threonine Kinases; C014026:hexamethylene bisacetamide