gsk1210151a has been researched along with Skin-Neoplasms* in 2 studies
2 other study(ies) available for gsk1210151a and Skin-Neoplasms
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Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT and YAP signaling.
Histone acetylation marks have an important role in controlling gene expression and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins and novel inhibitiors of these proteins are currently in clinical development. Inhibitors of HDAC and BET proteins have individually been shown to cause apoptosis and reduce growth of melanoma cells. Here we show that combining the HDAC inhibitor LBH589 and BET inhibitor I-BET151 synergistically induce apoptosis of melanoma cells but not of melanocytes. Induction of apoptosis proceeded through the mitochondrial pathway, was caspase dependent and involved upregulation of the BH3 pro-apoptotic protein BIM. Analysis of signal pathways in melanoma cell lines resistant to BRAF inhibitors revealed that treatment with the combination strongly downregulated anti-apoptotic proteins and proteins in the AKT and Hippo/YAP signaling pathways. Xenograft studies showed that the combination of inhibitors was more effective than single drug treatment and confirmed upregulation of BIM and downregulation of XIAP as seen in vitro. These results support the combination of these two classes of epigenetic regulators in treatment of melanoma including those resistant to BRAF inhibitors. Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Epigenesis, Genetic; Female; Heterocyclic Compounds, 4 or More Rings; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Immunohistochemistry; Indoles; Melanocytes; Melanoma; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondria; Neoplasm Transplantation; Panobinostat; Phosphoproteins; Protein Structure, Tertiary; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Signal Transduction; Skin Neoplasms; Transcription Factors; YAP-Signaling Proteins | 2015 |
Control of NF-kB activity in human melanoma by bromodomain and extra-terminal protein inhibitor I-BET151.
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. Topics: Animals; Apoptosis; Autocrine Communication; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chemokines; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Heterocyclic Compounds, 4 or More Rings; Humans; Interleukin-6; Interleukin-8; Melanoma; Mice; NF-kappa B; Protein Serine-Threonine Kinases; Skin Neoplasms; Transcription Factors | 2014 |