Abstract
ABSTRACT (1) Background: BET bromodomain proteins regulate transcription by binding acetylated histones and attracting key factors for, e.g., transcriptional elongation. BET inhibitors have been developed to block pathogenic processes such as cancer and inflammation. Despite having potent biological activities, BET inhibitors have still not made a breakthrough in clinical use for treating cancer. Multiple resistance mechanisms have been proposed but thus far no attempts to block this in glioma has been made. (2) Methods: Here, we have conducted a pharmacological synergy screen in glioma cells to search for possible combination treatments augmenting the apoptotic response to BET inhibitors. We first used HMBA, a compound that was developed as a differentiation therapy four decades ago but more recently was shown to primarily inhibit BET bromodomain proteins. Data was also generated using other BET inhibitors. (3) Results: In the synergy screen, we discovered that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and human glioma cells in vitro as well as in vivo xenografts. The combination is not unique to HMBA but also other BET inhibitors such as JQ1 and I-BET-762 can synergize with MEK inhibitors. (4) Conclusions: Our findings validate a combination therapy previously demonstrated to exhibit anti-cancer activities in multiple other tumour types but which appears to have been lost in translation to the clinic.
Highlights
Before the discovery of oncogenes the concept of cancer cell differentiation therapy was explored therapeutically, in part based on early observations that dimethylsulfoxide (DMSO) can cause differentiation of Friend virus induced mouse erythroleukemia (MEL) cells into hemoglobin producing red blood cells [1]
(3) Results: In the synergy screen, we discovered that several MEK inhibitors can enhance apoptosis in response to hexamethylene bisacetamide (HMBA) in rat and human glioma cells in vitro as well as in vivo xenografts
Our findings validate a combination therapy previously demonstrated to exhibit anticancer activities in multiple other tumor types but which appears to have been lost in translation to the clinic
Summary
Before the discovery of oncogenes the concept of cancer cell differentiation therapy was explored therapeutically, in part based on early observations that dimethylsulfoxide (DMSO) can cause differentiation of Friend virus induced mouse erythroleukemia (MEL) cells into hemoglobin producing red blood cells [1]. Efforts to produce more potent cancer differentiation compounds generated two molecules that were tested in the clinic, hexamethylene bisacetamide (HMBA) and suberoylanilide hydroxamic acid (SAHA, later renamed to vorinostat) [2, 3]. We discovered that HMBA is a bromodomain and extra-terminal domain (BET) inhibitor, with highest binding affinity for bromodomain 2 (BD2) of BET proteins BRD2, BRD3 and BRD4 while inhibiting the bromodomain of histone acetyltransferase. HMBA was likely the first anti-cancer compound used in the clinic that inhibited BET bromodomain proteins, the concept of BET inhibitors (BETis) were largely popularized with the development of the low nanomolar BETis JQ1 and iBET-151 [7, 8]. The mechanism of action of these compounds involves inhibition of transcriptional elongation [9, 10].
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