Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity

Elife. 2016 May 31;5:e11156. doi: 10.7554/eLife.11156.

Abstract

Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-κB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs.

Keywords: acetylation; diflunisal; histone acetyltransferase; human biology; medicine; salicylate.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetyl Coenzyme A / antagonists & inhibitors
  • Acetyl Coenzyme A / metabolism
  • Acetylation / drug effects
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding, Competitive
  • Catalytic Domain
  • Cell Line, Tumor
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Diflunisal / chemistry
  • Diflunisal / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Leukemic*
  • HEK293 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Leukocytes / drug effects
  • Leukocytes / enzymology
  • Leukocytes / pathology
  • Mice
  • Mice, SCID
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Protein Binding
  • RUNX1 Translocation Partner 1 Protein / genetics
  • RUNX1 Translocation Partner 1 Protein / metabolism
  • Salicylic Acid / chemistry
  • Salicylic Acid / pharmacology*
  • Signal Transduction
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays
  • p300-CBP Transcription Factors / antagonists & inhibitors*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • AML1-ETO fusion protein, human
  • Antineoplastic Agents
  • Core Binding Factor Alpha 2 Subunit
  • Enzyme Inhibitors
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • Acetyl Coenzyme A
  • Diflunisal
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Salicylic Acid