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  • br LOX in pancreatic cancer LOX is a key player

    2024-04-15


    5-LOX in pancreatic cancer 5-LOX is a key player in pancreatic cancer (PC) progression. The upregulation of 5-LOX mRNA has been observed in pancreatic adenocarcinoma (PDAC) and also in neoplastic pancreatic tissues (Kennedy et al., 2003). Higher levels of 5-LOX transcripts (messengers) are present in malignant PC cell lines and these factors were absent in healthy human PC cell lines (Hennig et al., 2002). They also revealed that the 5-LOX downstream metabolite, known as LTB4, was also significantly upregulated in PC tissues (Hennig et al., 2002). Various 5-LOX inhibitors like NDGA, Rev5901, and MK-886 (FLAP inhibitor) inhibited the thymidine assimilation-an indication of the induced growth inhibition in PC cell lines (Ding et al., 1999). AA and linoleic Andarine receptor also stimulate PC cell proliferation (Ding et al., 1999). Ding et al. (Ding et al., 2003) revealed that 5-HETE displays mitogenic effects by initiating PC cell survival in a time and dose-dependent manner. Furthermore, Tong et al. (Tong et al., 2002b) defined that a mitochondria-mediated signaling pathway causes apoptosis induced by LOX inhibition in PC cell lines. They also revealed that expression levels of Bcl-2 and Mcl-2 decreased, whereas expression levels of Bax were elevated by LOX inhibitors in PC cell lines. LOX inhibitors increased the cytochrome-c production and activation of caspase-9 (Tong et al., 2002b). in vivo, LOX inhibitors were successfully able to block PC progression and induce apoptosis (Tong et al., 2002b). LTB4 is known to improve cell-to-cell adhesion and the movement of neutrophils towards vascular endothelium (Ding et al., 2005). LTB4 is secreted from PC cell lines, and its receptors are increased in PC tissue and PC cells (Hennig et al., 2002; Tong et al., 2002a). The two GPCRs that have high and low affinities for LTB4 are BLT1 and BLT2, respectively (Adrian et al., 2008). 5-LOX along with BLT1 and BLT2 are known to upregulate in PC cell lines suggesting that LTB4 and its receptors are potential therapeutic targets in PC treatment (Hennig et al., 2008). LY293111 is a LTB4 receptor antagonist that inhibits PC proliferation and progression as well as inducing apoptosis by blocking the LTB4-mediated kinase phosphorylation in multiple PC cell lines (Ding et al., 2005). A study found that LY293111 caused cell cycle arrest in the S stage and suppressed cdk2, cyclin A, and E expression levels (Tong et al., 2007). Another study conducted on an animal model revealed that LY293111 suppressed tumor growth in subcutaneous human PC xenografts (Tong et al., 2002a). The combination of a COX-2 inhibitor, known as celecoxib, plus a 5-LOX inhibitor, known as MK886, effectively decreases tumor progression in PC by decreasing BLT1 and VEGF. The expression levels of ERK are induced in PC cell line treatment via a COX-2 inhibitor (Ding et al., 2011); the consecutive treatment includes the use of the 5-LOX inhibitor, however, inhibited tumor progression, indicating that the 5-LOX inhibitor enhances the anti-tumorous properties of COX-2 inhibitor.
    5-LOX in hepatocellular carcinoma Various malignancies including hepatocellular carcinoma (HCC) have been associated with elevated expression of 5-LOX and its metabolites. Investigations regarding xenografts have revealed that administration of Zileuton (5-LOX inhibitor), cause a significant reduction in the nodule and a decrease in the number of nodes (Xu et al., 2011). This reduction indicates that 5-LOX inhibition could serve as a potential anti-cancerous approach in the treatment regimen of HCC patients. Blocking the activity of 5-LOX has been associated with decreased cell amplification and stimulated cell death (apoptosis) in several types of malignant cell lines (Gunning et al., 2002). In the case of HCC, 5-LOX inhibition decreased cell capability and also increased apoptosis (cell death) in Andarine receptor a time and dose-dependent manner by decreasing the Bcl-2/Bax ratio (Tang et al., 1996), altering the mitochondrial permeability (Ghosh and Myers, 1998), and activating the c-Jun (Ghosh, 2003). Therefore, 5-LOX is an essential enzyme for HCC progression, and the inhibition of 5-LOX activity could serve as an effective chemo-preventive option for HCC treatment.