Abstract
The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies worldwide
As Caco-2 cells displayed no natnatdiv1e.4b-flooltds gene-1 (NAG1) immunoreactivity, we examined oxicam’s effect on their expression of NFKBIA, MYD88 and RELA, i.e., genes associated with NF-κB signaling, known to control Monocyte chemoattractant proteins (MCPs) and Macrophage inflammatory proteins (MIPs) expression as well as being regulated by non-steroidal anti-inflammatory drug (NSAID)
Synthesized analogues of the oxicam class of NSAIDs labeled with reduced gastrotoxicity, differing from piroxicam and meloxicam with an arylpiperazine moiety at the thiazine ring, are able to downregulate MCP and MIP chemokines to varying degrees, while the classic oxicams had a mostly negligible or non-significant effect on their expression and secretion
Summary
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Its incidence is higher among individuals with a history of polyps and patients with inflammatory bowel disease [1]. Chemokines, which are involved in immune cell trafficking, constitute a link between inflammation and cancer They mediate interactions between tumor and stromal cells via their respective 7-transmembrane-spanning G protein-coupled receptors, facilitating cancer angiogenesis, invasion, and metastasis. As such, their signaling pathways are currently under investigation either as potential targets for immunotherapies or, on the contrary, as therapeutics (reviewed in [2]). MCP chemokines are expressed mainly by cancer cells, but their expression by tumorassociated macrophages (TAMs), cancer-associated fibroblasts (CAFs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and mesenchymal stem cells (MSCs) has been reported (reviewed in [3]). In CRC, an overexpression of MCPs has been associated with a worse prognosis, while that of MIPs has been associated with a better prognosis (reviewed in [3,4])
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