Control of NF‐kB activity in human melanoma by bromodomain and extra‐terminal protein inhibitor I‐BET151

Abstract

The transcription factor NF-kappaB (NF-kB) is a key regulator of cytokine and chemokine production in melanoma and is responsible for symptoms such as anorexia, fatigue, and weight loss. In addition, NF-kB is believed to contribute to progression of the disease by upregulation of cell cycle and anti-apoptotic genes and to contribute to resistance against targeted therapies and immunotherapy. In this study, we have examined the ability of the bromodomain and extra-terminal (BET) protein inhibitor I-BET151 to inhibit NF-kB in melanoma cells. We show that I-BET151 is a potent, selective inhibitor of a number of NF-kB target genes involved in induction of inflammation and cell cycle regulation and downregulates production of cytokines such as IL-6 and IL-8. SiRNA studies indicate that BRD2 is the main BET protein involved in regulation of NF-kB and that I-BET151 caused transcriptional downregulation of the NF-kB subunit p105/p50. These results suggest that BET inhibitors may have an important role in treatment of melanoma where activation of NF-kB may have a key pathogenic role.

Expression of the class 1 histone deacetylases HDAC8 and 3 are associated with improved survival of patients with metastatic melanoma

“…16 Previously, we showed that activation of NF-kB was associated with resistance of melanoma to the BRAF inhibitor vemurafenib. 27 Our studies support a possible role for regulation by NFkB, in that HDAC-1 and -8 were correlated with expression of NF-kB. These results appeared clinically significant in that nuclear NF-kB was associated with a shorter duration from the development of primary melanoma to the development of stage IV metastases and to death.…”

Targeting BET Bromodomains for Cancer Treatment

“…In vivo, the progression of the A375 melanoma xenograft is inhibited by MS417 and the number of metastases is markedly reduced. I-BET151 also impairs melanoma cell proliferation in vitro and in vivo [75,76]. Downregulation of NF-κB target genes was evidenced, mainly linked to BRD2.…”

“…Several bromodomain proteins, including BRD4 and BRD2, are over-expressed in glioblastoma [76,77]. Treatment with JQ1 reduces proliferation of orthotopic glioblastoma models while downregulation of c-Myc and BCL2 is observed in cell lines derived from this tumor type [75].…”

“…It is derived from a hit discovered in a cellular high-throughput screening assay designed for the identification of ApoA1 up-regulators. It has been extensively tested and found to possess anti-inflammatory and antitumor activity in a number of in vivo models [76,78,110].…”

Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery

“…Similar with I-BET762, I-BET151 also inhibits myeloma cell proliferation through inducing apoptosis and exerting strong anti-proliferative effect in vitro and in vivo through transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to transcriptional activator PTEFb [77]. BRD2 is the main BET protein involved in regulation of NF-kB and that I-BET151 caused transcriptional downregulation of the NF-kB subunit p105/p50 [80]. …”