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

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

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Azepines / pharmacology*
  • Benzodiazepines / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Ceruletide
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nitric Oxide / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatitis / chemically induced
  • Pancreatitis / drug therapy
  • Pancreatitis / immunology
  • Pancreatitis / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-myc / metabolism
  • RAW 264.7 Cells
  • Signal Transduction / drug effects
  • Triazoles / pharmacology*

Substances

  • (+)-JQ1 compound
  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Azepines
  • Cytokines
  • Inflammation Mediators
  • MYC protein, human
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Triazoles
  • Benzodiazepines
  • Nitric Oxide
  • molibresib
  • Ceruletide
  • Extracellular Signal-Regulated MAP Kinases