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  • br LOX in esophageal cancer Various studies suggest that abn

    2024-04-02


    5-LOX in esophageal cancer Various studies suggest that abnormal levels of AA metabolites play an essential role in human esophageal adenocarcinogenesis (EAC). The key AA derivatives of 5-LOX signaling molecules namely include, 5-HETE, LTB4, and cysteinyl LTs, which are well-known to initiate inflammatory pathways, proliferation, vascular absorptivity, and tightening of smooth muscle tissues in EAC patients (Hwang et al., 2002). Normal human esophageal tissues regulate 5-LOX function and produce adequate quantities of LTB4 (Chen and Yang, 2001). But, in the case of malignant EAC tissues, the levels of LTB4 increase remarkably (Hong et al., 2004a, 2004b), suggesting the involvement of the 5-LOX and AA pathways are vital biomarkers in EAC patients. Inhibiting AA metabolism by 5-LOX inhibitors is a key mechanism in restraining EAC (Zhi et al., 2003a, 2003b). The mixture of COX-2 inhibitor and 5-LOX inhibitor as advanced therapeutic strategies in the treatment regimen of EAC patients has exhibited some significant effects by inducing apoptosis. A recent study revealed that the combination of zileuton (5-LOX inhibitor) and celecoxib (COX-2 inhibitor) was successfully able to suppress LTB4 ionomycin mg and regress EAC tumor progression in vivo (Chen et al., 2004). This study evidently indicates that targeting 5-LOX as well as COX-2 signaling pathway could be effective in inhibiting the EAC development. Another study revealed that LTB4, a 5-LOX metabolite, is capable of reversing the effects of inhibitors of 5-LOX, which induces apoptosis in EAC cells. PPAR-γ activation or LTB4R-1 inhibition by LY293111 allows for repression of LTB4 production by suppressing proliferation and inducing apoptosis in EAC cell lines (Budman and Calabro, 2004). This mechanism is linked to fewer EAC cases and hence is considered a new therapeutic approach in treating EAC (Zhi et al., 2003a, 2003b).
    5-LOX in gastric cancer AA is cleaved by phospholipases from the membrane phospholipids. It is catalyzed by cyclooxygenase (COX) or by LOX. Human gastric cancer (GC) cell lines are known to metabolize AA, especially through the LOX signaling pathway instead of the COX pathway (Hong et al., 2001). AA is converted into HPTE (hydroperoxyeicosatetraenoic) acid and ultimately to either HETE or to LTs by lipoxygenase 5-LOX (Poff and Balazy, 2004). GC progression is inhibited by prostaglandins, PGD2 and PGE2, and it is stimulated by leukotrienes, LTC4 and LTD4 (Ye et al., 2005). 5-LOX expression is known to be elevated in GC tissues compared to other adjacent non-tumorous tissues (Ye et al., 2005). This study also revealed that inhibition of 5-LOX resulted a time and dose dependent stimulation of cell death, but no effect was observed on the 5-LOX messenger and protein expressions (Ye et al., 2005). Another study inspected the function of a 12-LOX metabolite, known as 12-HETE, in GC progression and instituted that 12-LOX inhibition reduced GC cell proliferation and induced apoptosis. 12-HETE also reversed the growth inhibition in GC cell lines (Wong et al., 2001). This suggests that the role of both 5-LOX and 12-LOX in GC development is crucial. It is possible that decreasing bcl-2 activity and stimulating caspase-7 activity is a signaling pathway that could potentially cause apoptosis in GC cell lines. Also, the decrease of AA metabolism induced by 12-LOX could serve as a novel strategy in designing new therapeutic approaches to GC. Curcumin, a natural anti-inflammatory agent, appears to block the activity of H. pylori, which is an infection linked to various pathological alterations including GC. Curcumin is known to block the NF-κB activation that is induced via H. pylori, gene expression of IL-8 (Park et al., 2007), and even aid in modulating AA metabolism such as PLA2, COX, and 5-LOX (Hong et al., 2004a, 2004b; Maheshwari et al., 2006). Similarly, red ginseng extract (RGE) is also capable of regulating H. pylori-stimulated NF-κB and IL-8 expression in GC cell lines through the regulation of 5-LOX (Nag et al., 2012). RGE was also able to downregulate 5-HETE synthesis and inhibit IL-8 gene expression by preventing 5-LOX as well as NF-κB DNA binding affinity.