Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

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.

Macrophage Inflammatory Proteins (MIPs) Contribute to Malignant Potential of Colorectal Polyps and Modulate Likelihood of Cancerization Associated with Standard Risk Factors

“…The authors presented the following chemokine expression patterns: N > A < T for CCL3, N = A < T for CCL4 and CXCL2, and N > A = T for CCL19. Regarding CCL3, it was indeed overexpressed in CRC, both locally-mRNA [25,26] and protein [27,30]-and at a systemic level [31,32]. It reflects the disease advancement [27,31] and, in particular, lymph node involvement [25].…”

“…Regarding CCL3, it was indeed overexpressed in CRC, both locally-mRNA [25,26] and protein [27,30]-and at a systemic level [31,32]. It reflects the disease advancement [27,31] and, in particular, lymph node involvement [25]. Functionally, CCL3 promotes cancer growth by stimulating proliferation, migration, and invasion, acting via the TRAF6/NF-κB pathway [27].…”

“…They are attributed to the chemokine impact on various populations of anti-tumor immune cells, including upregulating the number of CD45 + leukocytes in the tumor [39] and recruiting cytotoxic T and NK cells into the tumor microenvironment (TME) [40,41]. CCL4 is also upregulated in CRC [25,30] and its systematic concentrations are elevated [31,32]. The chemokine acts similarly to CCL3 with respect to being a promoter of cancer cell proliferation and survival [33] and a facilitator of metastasis [37,42].…”

“…They can either facilitate it, by promoting the proliferation, survival, and migration of cancer cells as well as angiogenesis, metastasis, and escape from immunosurveillance, or impede it by attracting anti-cancer proinflammatory subsets of immune cells. We have previously explored MIPs' association with CRC and demonstrated the ability of novel oxicam analogues to modulate MIPs' expression and secretion by colorectal adenocarcinoma cell lines [25]. Herein, we pursued MIPs' relationship with precancerous polyps by determining their expression patterns in transformed and non-transformed tissue, at the transcript and protein level, with reference to known malignancy risk factors to assess their relevance for risk stratification and chemotherapy.…”

An Efficient Synthesis of a Highly Functionalized Dihydrobenzo­thiophene Derivative: A Ring-Contracted Analogue of the Anti-inflammatory Drug Propoxicam

“…1,2 Since inflammation is crucial to the development and modulation of degenerative diseases, including neurodegenerative and cardiovascular diseases, diabetes and cancer, it is not surprising that oxicams have also found application in these areas. In particular, a growing body of evidence shows their potential role in the treatment of cancer 3 and in neurodegenerative processes such as Alzheimer's and Parkinson's diseases, as well as amyotrophic lateral sclerosis. 4 Moreover, members of the oxicam group have been shown to induce membrane fusion at physiologically relevant concentrations, a property that has attracted considerable attention.…”