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吡罗昔康、美洛昔康和奥昔康类似物对结直肠癌中巨噬细胞相关趋化因子的调节作用。

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

机构信息

Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland.

Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland.

出版信息

Molecules. 2021 Dec 5;26(23):7375. doi: 10.3390/molecules26237375.

DOI:10.3390/molecules26237375
PMID:34885960
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8659253/
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 , , , and as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated 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 and downregulated . They inhibited and and their effect on and 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 and were not upregulated in tumors, nor was in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, and were upregulated, while , and were downregulated in tumors. Tumor and increased along with advancing T and and 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 and interfering with NF-κB signaling.

摘要

氧杂蒽酮类药物的抗肿瘤作用机制尚未完全阐明。我们旨在评估经典和新型氧杂蒽酮类药物对结直肠腺癌细胞中巨噬细胞相关趋化因子（RTqPCR/Luminex xMAP）表达/分泌的影响，以及对非甾体抗炎药（NSAID）激活基因 、 、 、 和趋化因子谱在结直肠肿瘤中的表达的影响。美洛昔康使 下调 9.9 倍，但其他经典氧杂蒽酮类药物的影响可以忽略不计/无统计学意义。带有芳基哌嗪和苯甲酰部分取代噻嗪环的新型类似物显著地在不同程度上调节趋化因子的表达，上调 NAG1 和 ，并下调 。它们抑制 和 ，其对 和 的作用取决于剂量和暴露时间。噻嗪和哌嗪氮之间的丙烯连接基和芳基哌嗪的一个氟取代基是特征最有效的类似物。只有 和 在肿瘤中未上调，与正常粘膜相比，在肿瘤相邻组织中也未上调 。与相邻组织相比， 、 、 和 在肿瘤中下调，而 、 和 在肿瘤中上调。肿瘤 、 和 随着 T 分期和 N 分期的进展而增加， 随着 分期的进展而增加。芳基哌嗪和苯甲酰部分引入氧杂蒽酮骨架可有效调节趋化因子的表达，其作用机制是上调 和干扰 NF-κB 信号。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/e931cc23d5d5/molecules-26-07375-g017.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/e931cc23d5d5/molecules-26-07375-g017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/0f4ae71ad471/molecules-26-07375-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/a5e52245a6f7/molecules-26-07375-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/4af975a89bb3/molecules-26-07375-g007a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/6f4a08569762/molecules-26-07375-g008a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/8dd652ad82c4/molecules-26-07375-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/f80a6f4a1472/molecules-26-07375-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/b96d50519e96/molecules-26-07375-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/0d1892ae8a2e/molecules-26-07375-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/cd2d2bd73d33/molecules-26-07375-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/d96ab56e0e1c/molecules-26-07375-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/deeb3554203b/molecules-26-07375-g015a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/08bab246788d/molecules-26-07375-g016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b9b/8659253/e931cc23d5d5/molecules-26-07375-g017.jpg

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