The Emerging Role of COX-2, 15-LOX and PPARγ in Metabolic Diseases and Cancer: An Introduction to Novel Multi-target Directed Ligands (MTDLs)

Rana    A.    Alaaeddine; Perihan    A.    Elzahhar; Ibrahim       AlZaim; Wassim       Abou-Kheir; Ahmed    S.F.    Belal; Ahmed    F.    El-Yazbi
doi:10.2174/0929867327999200820173853
Abstract

Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro- and antitumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarizing the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.
Keywords: Multi-target directed ligands, cyclooxygenase-2, 15-lipooxygenase, peroxisome proliferator-activated receptor gamma, adipose inflammation, vascular dysfunction, cancer, neurodegenerative disease.
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DOI https://dx.doi.org/10.2174/0929867327999200820173853	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

The Emerging Role of COX-2, 15-LOX and PPARγ in Metabolic Diseases and Cancer: An Introduction to Novel Multi-target Directed Ligands (MTDLs)

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