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.
Highlights
The idea of tumor cell differentiation was conceptualized when Charlotte Friend showed that the solvent DMSO was capable of inducing differentiation of virus-induced mouse erythroleukemia (MEL) cells [1]
Consistent with the hypothesis that hexamethylene bisacetamide (HMBA) could be a BET inhibitor, molecular docking in silico shows that HMBA fits the same pocket in BD2 of BRD2 as JQ1 (Supplementary Fig. S1A)
Of interest is that HMBA makes a hydrogen bond with His395 in one of the subunits. Because this position is conserved in the BC-loop of the BD2 domain of all BET proteins, and as BD1 has an Asp at the corresponding position [20], it is tempting to speculate that this is the reason behind the apparent BD2 selectivity of HMBA
Summary
The idea of tumor cell differentiation was conceptualized when Charlotte Friend showed that the solvent DMSO was capable of inducing differentiation of virus-induced mouse erythroleukemia (MEL) cells [1]. Because the FDA had banned DMSO for human use, Tanaka and colleagues [2] initiated a search for polar compounds that would be able to induce MEL cell differentiation at lower concentrations. Parallel to the development of HMBA, Richon and colleagues [8] discovered the target of a much more potent MEL differentiation agent, suberoylanilide hydroxamic acid (SAHA). They demonstrated that SAHA is a potent inhibitor of histone deacetylases (HDAC), which spawned active investigations and clinical development. SAHA, or vorinostat, is FDAapproved for treatment of cutaneous T-cell leukemia [9] and other HDAC inhibitors are approved for use in other tumor types. The target of HMBA remained elusive though [10] because Richon
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