Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Prostaglandins Other Lipid Mediat. 2011 Nov;96(1-4):37-40. doi: 10.1016/j.prostaglandins.2011.06.005. Epub 2011 Jul 6.
NSAIDs are known to be inhibitors of cyclooxygenase-2 (COX-2) accounting for their anti-inflammatory and anti-tumor activities. However, the anti-tumor activity cannot be totally attributed to their COX-2 inhibitory activity as these drugs can also inhibit the growth and tumor formation of COX-2-null cell lines. Several potential targets aside from COX-2 for NSAIDs have been proposed. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH), a key prostaglandin catabolic enzyme, was recently shown to be a tumor suppressor. Effects of NSAIDs on 15-PGDH expression were therefore studied. Flurbiprofen, indomethacin and other NSAIDs stimulated 15-PGDH activity in colon cancer HT29 cells as well as in lung cancer A549 cells and glioblastoma T98G cells. (R)-flurbiprofen and sulindac sulfone, COX-2 inactive analogs, also stimulated 15-PGDH activity indicating induction of 15-PGDH is independent of COX-2 inhibition. Stimulation of 15-PGDH expression and activity by NSAIDs was examined in detail in colon cancer HT29 cells using flurbiprofen as a stimulant. Flurbiprofen stimulated 15-PGDH expression and activity by increasing transcription and translation and by decreasing the turnover of 15-PGDH. Mechanism of stimulation of 15-PGDH expression is not clear. Protease(s) involved in the turnover of 15-PGDH remains to be identified. However, flurbiprofen down-regulated matrix metalloproteinase-9 (MMP-9) which was shown to degrade 15-PGDH, but up-regulated tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9 contributing further to a slower turnover of 15-PGDH. Taken together, NSAIDs may up-regulate 15-PGDH by increasing the protein expression as well as decreasing the turnover of 15-PGDH in cancer cells.
非甾体抗炎药（NSAIDs）已知是环氧化酶-2（COX-2）的抑制剂，这解释了它们的抗炎和抗肿瘤活性。然而，这些药物的抗肿瘤活性不能完全归因于其 COX-2 抑制活性，因为它们还可以抑制 COX-2 缺失细胞系的生长和肿瘤形成。除了 COX-2 之外，NSAIDs 还有其他几个潜在的靶点。15-羟基前列腺素脱氢酶（15-PGDH），一种关键的前列腺素分解代谢酶，最近被证明是一种肿瘤抑制因子。因此，研究了 NSAIDs 对 15-PGDH 表达的影响。氟比洛芬、吲哚美辛和其他 NSAIDs 刺激结肠癌 HT29 细胞以及肺癌 A549 细胞和神经胶质瘤 T98G 细胞中的 15-PGDH 活性。（R）-氟比洛芬和舒林酸砜，COX-2 无活性类似物，也刺激 15-PGDH 活性，表明 15-PGDH 的诱导与 COX-2 抑制无关。使用氟比洛芬作为刺激物，在结肠癌 HT29 细胞中详细研究了 NSAIDs 对 15-PGDH 表达和活性的刺激作用。氟比洛芬通过增加转录和翻译以及减少 15-PGDH 的周转率来刺激 15-PGDH 的表达和活性。刺激 15-PGDH 表达的机制尚不清楚。参与 15-PGDH 周转率的蛋白酶仍有待确定。然而，氟比洛芬下调基质金属蛋白酶-9（MMP-9），后者被证明可降解 15-PGDH，但上调组织金属蛋白酶抑制剂-1（TIMP-1），后者是 MMP-9 的抑制剂，进一步导致 15-PGDH 的周转率更慢。综上所述，NSAIDs 可能通过增加癌症细胞中 15-PGDH 的蛋白表达以及减少其周转率来上调 15-PGDH。
