Cho H, Tai H-H
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Prostaglandins Leukot Essent Fatty Acids. 2002 Dec;67(6):461-5. doi: 10.1054/plef.2002.0457.
15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD(+)-dependent oxidation of 15(S)-hydroxyl group of prostaglandins and has been considered a key enzyme involved in biological inactivation of prostaglandins. This enzyme is markedly induced by androgens in hormone-sensitive human prostate cancer cells (Tong M., Tai H. H. Biochem Biophys Res Commun 2000; 276: 77-81) and may be involved in tumorigenesis. Inhibition of this enzyme may be of value in anticancer therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit cyclooxygenases (COXs) have been shown to be chemopreventive in epidemiological and animal-model studies. However, chemoprevention by these drugs may not be directly related to their inhibition of COXs. Other targets may be also involved in their chemopreventive activity. We have examined a variety of NSAIDs including COX-2 selective inhibitors, peroxisome proliferator-activated receptor (PPAR) gamma agonists and phytophenolic compounds which have been shown to be chemopreventive for their effect on 15-PGDH. It was found that most of these compounds were potent inhibitors of 15-PGDH. Among these compounds, ciglitazone appeared to be the most powerful inhibitor (IC(50)=2.7 microM). Inhibition by ciglitazone was non-competitive with respect to NAD(+) and uncompetitive with respect to PGE(2).
15-羟基前列腺素脱氢酶（15-PGDH）催化前列腺素15（S）-羟基的NAD（+）依赖性氧化，被认为是参与前列腺素生物失活的关键酶。该酶在激素敏感的人前列腺癌细胞中被雄激素显著诱导（童M.，戴H.H.生物化学与生物物理研究通讯2000；276：77-81），可能参与肿瘤发生。抑制该酶在抗癌治疗中可能具有价值。在流行病学和动物模型研究中，已证明抑制环氧化酶（COXs）的非甾体抗炎药（NSAIDs）具有化学预防作用。然而，这些药物的化学预防作用可能与其对COXs的抑制作用没有直接关系。其他靶点可能也参与了它们的化学预防活性。我们研究了多种NSAIDs，包括COX-2选择性抑制剂、过氧化物酶体增殖物激活受体（PPAR）γ激动剂和植物酚类化合物，这些化合物已被证明具有化学预防作用，研究它们对15-PGDH的影响。发现这些化合物中的大多数是15-PGDH的有效抑制剂。在这些化合物中，吡格列酮似乎是最有效的抑制剂（IC50 = 2.7 microM）。吡格列酮的抑制作用对NAD（+）是非竞争性的，对PGE2是反竞争性的。
