New approaches to cancer therapy: combining Fatty Acid Amide Hydrolase (FAAH) inhibition with Peroxisome Proliferator-Activated Receptors (PPARs) activation.

Over the course of the last decade, Peroxisome Proliferator-Activated Receptors (PPARs) have been identified as part of the cannabinoid signaling system: both phytocannabinoids and endocannabinoids are capable of binding and activating these nuclear receptors. Fatty Acid Amide Hydrolase (FAAH) hydrolyzes the endocannabinoid Anandamide and other N-Acylethanolamines. These substances have been shown to have numerous anti-cancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPARα subtype and by PPARγ subtype, especially antiproliferation and activation of apoptosis. The substrates of FAAH are also PPAR agonists, which explains the PPAR-mediated effects of FAAH inhibitors. Much like cannabinoid ligands and FAAH inhibitors, PPARγ agonists show antiproliferative effects on cancer cells, suggesting that additive or synergistic effects may be achieved through the positive modulation of both signaling systems. In this perspective, we discuss the development of novel FAAH inhibitors able to directly act as PPAR agonists and their promising utilization as leads for the discovery of highly effective anti-cancer compounds.