Lipoxygenase Inhibitors as Cancer Chemopreventives: Discovery, Recent Developments and Future Perspectives

Abstract

Background: Leukotrienes (LTs) constitute a bioactive group of Polyunsaturated Fatty Acid (PUFA) metabolites molded by the enzymatic activity of lipoxygenase (LO) and have a pivotal role in inflammation and allergy. Evidence is accumulating both by in vitro cell culture experiments and animal tumor model studies in support of the direct involvement of aberrant metabolism of arachidonic acid (ACD) in the development of several types of human cancers such as lung, prostate, pancreatic and colorectal malignancies. Several independent experimental data suggest a correlation between tumoral cells viability and LO gene expression, especially, 5-lipoxygenase (5-LO). Overexpressed 5-LO cells live longer, proliferate faster, invade more effectively through extracellular matrix destruction and activate the anti-apoptotic signaling mechanisms more intensively compared to the normal counterparts. Thus, some groups of lipoxygenase inhibitors may be effective as promising chemopreventive agents.

Methods: A structured search of bibliographic databases for peer-reviewed research literature regarding the role of LO in the pathogenesis of cancer was performed. The characteristics of screened papers were summarized and the latest advances focused on the discovery of new LO inhibitors as anticancer agents were discussed.

Results: More than 180 papers were included and summarized in this review; the majority was about the newly designed and synthesized 5-LO inhibitors as anti-inflammatory and anticancer agents. The enzyme's structure, 5-LO pathway, 5-LO inhibitors structure-activity relationships as well as the correlation between these drugs and a number of most prevalent human cancers were described. In most cases, it has been emphasized that dual cyclooxygenase-2/5-lipoxygenase (COX-2/5-LO) or dual 5-lipoxygenase/microsomal prostaglandin E synthase-1 (5-LO/mPGES-1) inhibitors possess considerable inhibitory activities against their target enzymes as well as potent antiproliferative effects. Several papers disclosing 5-lipoxygenase activating protein (FLAP) antagonists as a new group of 5-LO activity regulators are also subject to this review. Also, the potential of 12-lipoxygenase (12- LO) and 15-lipoxygenase (15-LO) inhibitors as chemopreventive agents was outlined to expand the scope of new anticancer agents discovery. Some peptides and peptidomimetics with anti-LT activities were described as well. In addition, the cytotoxic effects of lipoxygenase inhibitors and their adverse effects were discussed and some novel series of natural-product-derived inhibitors of LO was also discussed in this review.

Conclusion: This review gives insights into the novel lipoxygenase inhibitors with anticancer activity as well as the different molecular pharmacological strategies to inhibit the enzyme effectively. The findings confirm that certain groups of LO inhibitors could act as promising chemopreventive agents.

Keywords: Cancer; Leukotrienes (LTs); Lipoxygenase inhibitors; Polyunsaturated Fatty Acid (PUFA); Structure-Activity Relationships (SAR); Synthesis.