New Approaches to Cancer Therapy: Combining Fatty Acid Amide Hydrolase (FAAH) Inhibition with Peroxisome Proliferator-Activated Receptors (PPARs) Activation
New Approaches to Cancer Therapy: Combining Fatty Acid Amide Hydrolase (FAAH) Inhibition with Peroxisome Proliferator-Activated Receptors (PPARs) Activation
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DOI：
10.1021/acs.jmedchem.9b00885
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发表时间：
2019-12-26
影响因子：
7.3
通讯作者：
Laghezza, Antonio
中科院分区：
文献类型：
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作者：
Brunetti, Leonardo;Loiodice, Fulvio;Laghezza, Antonio
在过去的十年中，过氧化物酶体增殖物激活受体（ppar）已被确定为大麻素信号系统的一部分：植物大麻素和内源性大麻素都能够结合并激活这些核受体。脂肪酸酰胺水解酶（FAAH）水解内源性大麻素anandamide和其他n -酰基乙醇胺。这些物质已被证明具有多种抗癌作用，事实上，抑制FAAH具有多种有益作用，这些作用是由PPAR α亚型和PPAR γ亚型介导的，特别是抗增殖和激活凋亡。FAAH的底物也是PPAR激动剂，这解释了FAAH抑制剂的PPAR介导作用。就像大麻素配体和FAAH抑制剂一样，PPAR γ激动剂对癌细胞显示出抗增殖作用，这表明可以通过积极调节这两种信号系统来实现附加或协同作用。在这篇文章中，我们讨论了能够直接作为PPAR激动剂的新型FAAH抑制剂的发展，以及它们作为发现高效抗癌化合物的线索的前景。
Over the course of the past 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 anticancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPAR alpha subtype and by PPAR gamma 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, PPAR gamma 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 Miniperspective, 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 anticancer compounds.