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Cancer Lett. 2017 May 28;394:76-87. doi: 10.1016/j.canlet.2017.02.021. Epub 2017 Feb 27.

Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer.

Author information

1
Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, NH, USA; Michigan State University, Department of Pharmacology & Toxicology, East Lansing, MI, USA.
2
Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, NH, USA.
3
Geisel School of Medicine at Dartmouth, Department of Microbiology and Immunology, Lebanon, NH, USA.
4
Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, NH, USA; Michigan State University, Department of Pharmacology & Toxicology, East Lansing, MI, USA. Electronic address: liby.kare@msu.edu.

Abstract

Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of selective, small molecule inhibitors that target BET (bromodomain and extra terminal) proteins. By impairing their ability to bind to acetylated lysines on histones, bromodomain inhibitors interfere with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. In this study, JQ1 and I-BET 762 decreased c-Myc and p-Erk 1/2 protein levels and inhibited proliferation in pancreatic cancer cells. The tumor microenvironment is known to play an important role in pancreatic cancer, and these drugs suppressed the production of nitric oxide and a variety of inflammatory cytokines, including IL-6, CCL2, and GM-CSF, in both immune and pancreatic cancer cells in vitro. Notably, the bromodomain inhibitors also reduced protein levels of p-Erk 1/2 and p-STAT3 in mouse models of pancreatic cancer. All of these proteins are essential for tumor promotion, progression and metastasis. In conclusion, the bromodomain inhibitors JQ1 and I-BET 762 targeted and suppressed multiple pathways in pancreatic cancer. I-BET 762 and a number of other bromodomain inhibitors are currently being tested in several clinical trials, making them potentially promising drugs for the treatment of pancreatic cancer, an often-fatal disease.

KEYWORDS:

Bromodomain inhibitors; Cytokines; Pancreatic cancer; Tumor microenvironment

PMID:
28254412
DOI:
10.1016/j.canlet.2017.02.021
[Indexed for MEDLINE]

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