Lipoxygenase (LOX) Inhibitors

Lipoxygenases (LOX) belong to a heterogenous family of lipid-peroxidizing enzymes and are involved in the biosynthesis of mediators of inflammation. Based on their regiospecificity during interaction with substrates, LOX have been classified as 5-, 8-, 12-, and 15-LOX. They insert oxygen at carbon 5, 8, 12 or 15 of arachidonic acid, forming 5S-, 8S-, 12S-, or 15S-hydroperoxyeicosatetraenoic acid (5-, 8-, 12-, or 15-HPETE). HPETEs can be further reduced by glutathione peroxidase to the hydroxy forms (5-, 8-, 12-, 15-HETE), respectively. 5-LOX is a dioxygenase that catalyzes the incorporation of molecular oxygen into arachidonic acid (oxygenase activity), producing HPETE and then forms the unstable epoxide LTA4 (LTA4 synthase activity). This is followed by the insertion of molecular oxygen at position C5, converting LTA4 to either 5(S)-hydroxy-6-trans-8, 11,14-cis-eicosatetranoic acid (5-HETE) or leukotrienes. Hydrolytic attack of LTA4 by leukotriene A4 hydrolase yields LTB4, a potent neutrophil chemoattractant and stimulator of leukocyte adhesion to endothelial cells. LTA4 can be conjugated with glutathione to form LTC4 by the action of LTC4 synthase. 5-LOX pathway has been implicated in the development and progression of human cancers. Hence, 5-LOX inhibitors have been sought for their chemopreventive effects. Inhibition of 5-LOX activity is shown to block prostate cancer cell proliferation. 12-LOX exists in three distinct forms: the leukocyte-type, the platelet-type, and the epidermal form. The platelettype 12-LOX converts arachidonic acid to 12-(S)-HETE. The leukocyte-type 12-LOX metabolizes arachidonic acid or linoleic acid to either 12(S)-HETE or 15(S)-HETE. The epidermal form of 12-LOX converts arachidonic acid to 12-HETE and 15-HETE. 12-LOX has been shown to be involved in both cancer cell proliferation and survival. Inhibition of 12-LOX blocks cell proliferation and induces apoptosis in carcinosarcoma cells. 8-LOX is expressed in the skin after irritation or treatment with tumor promoters. Compared with other LOX enzymes, 8-LOX has received little attention for its role in carcinogenesis and cancer growth. 15-LOX exists as two isozymes, 15-LOX-1 and 15-LOX-2. It converts arachidonic acid to 15-HPETE which is then reduced by glutathione peroxidase to 15-HETE. The preferred substrate for 15-LOX-1 and 15-LOX-2 are linoleic acid and arachidonic acid, respectively. The 15- LOX-1 product, 13-S-HODE, is reported to enhance cell proliferation and potentiate the mitogenic response to EGF in different cell types. 15-LOX has also been implicated in the pathogenesis of altherosclerosis.

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