Lovering Andrew L, Ride Jon P, Bunce Christopher M, Desmond Julian C, Cummings Stephen M, White Scott A
The School of Biosciences, The University of Birmingham, Birmingham, United Kingdom.
Cancer Res. 2004 Mar 1;64(5):1802-10. doi: 10.1158/0008-5472.can-03-2847.
It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
越来越多的确凿证据表明，非甾体抗炎药（NSAID）可预防胃肠道肿瘤，也可能预防多种其他肿瘤。这些作用广泛归因于对环氧化酶（COX）的抑制，尤其是COX-2。然而，一些观察结果表明可能涉及其他靶点。除了作用于COX外，某些NSAID还抑制属于醛糖还原酶（AKR）家族的酶，包括AKR1C3。我们之前已经证明，AKR1C3的过表达会抑制骨髓细胞的细胞分化并促进其增殖。然而，这种酶具有广泛的组织分布，因此是NSAID非COX依赖性抗肿瘤作用靶点的新候选者。在此，我们报告了与NSAID吲哚美辛（分辨率1.8 Å）或氟芬那酸（分辨率1.7 Å）复合的AKR1C3的X射线晶体结构。一个吲哚美辛分子结合在活性位点，而氟芬那酸既结合在活性位点，也结合在中央β桶另一端的β发夹环上。另外两个晶体结构（分辨率1.20和2.1 Å）显示乙酸盐结合在活性位点，占据了假定的氧负离子孔。这些数据强调AKR1C3是NSAID的非COX依赖性靶点，并将为未来开发具有减少COX依赖性副作用的新癌症疗法提供结构基础。
