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

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From: eLife(Vol. 5)
Publisher: eLife Science Publications, Ltd.
Document Type: Report
Length: 13,139 words
Lexile Measure: 1530L

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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-[kappa]B 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. DOI: http://dx.doi.org/10.7554/eLife.11156.001 eLife digest People have been using a chemical called salicylate, which was once extracted from willow tree bark, as medicine for pain, fever and inflammation since ancient Greece. Aspirin is derived from salicylate but is a more potent drug. Aspirin exerts its anti-inflammatory effect by shutting down the activity of proteins that would otherwise boost inflammation. Aspirin achieves this by releasing a chemical marker, called an acetyl group, to be added to these proteins via a process known as protein acetylation. However, salicylate cannot trigger protein acetylation and so it was not clear how it reduces inflammation. An anti-diabetes drug that is converted into salicylate in the body reduces inflammation by inhibiting a protein called NF-[kappa]B. In 2001, a group of researchers reported that NF-[kappa]B becomes active when an enzyme called p300 adds an acetyl group to it. This raised the question: does salicylate reduce inflammation by blocking, instead of triggering, protein acetylation. Now, Shirakawa et al. -- who include a researcher involved in the 2001 study -- show that salicylate does indeed block the activity of the p300 enzyme. Shirakawa et al. then searched a database looking for drugs that have salicylate as part of their molecular structure. The search led to a drug called diflunisal, which was even more effective at blocking p300 in laboratory tests. Some cancers, including a blood cancer, rely on p300 to grow; diflunisal was shown to stop this kind of cancer cell from growing, both in the laboratory and in mice. Together, the experiments suggest that salicylate and drugs that share some of its structure might represent useful treatments for certain cancers, as well as other diseases that involve the p300 enzyme. DOI: http://dx.doi.org/10.7554/eLife.11156.002

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Gale Document Number: GALE|A473276332