Enhanced sensitivity of bladder cancer cells to cisplatin mediated cytotoxicity and apoptosis in vitro and in vivo by the selective cyclooxygenase-2 inhibitor JTE-522.
Enhanced sensitivity of bladder cancer cells to cisplatin mediated cytotoxicity and apoptosis in vitro and in vivo by the selective cyclooxygenase-2 inhibitor JTE-522.
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DOI：
10.1097/01.ju.0000131945.74377.ad
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发表时间：
2004-10
期刊：
影响因子：
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通讯作者：
Y. Mizutani;H. Nakanishi;Yong Nan Li;N. Sato;A. Kawauchi;T. Miki
中科院分区：
文献类型：
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作者：
Y. Mizutani;H. Nakanishi;Yong Nan Li;N. Sato;A. Kawauchi;T. Miki
环氧合酶-2（Cyclooxygenase-2，考克斯-2）是一种重要的诱导酶，参与了前列腺素的合成，其抑制剂可诱导多种肿瘤细胞凋亡。几种抗癌剂也介导细胞凋亡，并且可能与考克斯-2抑制剂共享导致细胞凋亡的共同细胞内途径。我们推断膀胱癌细胞与考克斯-2抑制剂和抗癌剂的联合治疗可能导致协同凋亡。我们研究了选择性考克斯-2抑制剂JTE-522（4-（4-环己基-2-甲基恶唑-5-基）-2-氟苯磺酰胺）是否与抗癌剂在体外和体内对膀胱癌细胞的细胞毒性和凋亡方面协同作用。材料与方法细胞毒性用微量培养四唑染料法测定。结果JTE-522与顺铂联合应用对T24膀胱癌细胞具有协同杀伤作用。JTE-522和CDDP在细胞毒性方面的协同作用是由于细胞凋亡。用JTE-522处理T24细胞降低抗凋亡分子Bcl-2的表达。JTE-522和CDDP对SCID小鼠异种移植的T24细胞系也有明显的体内生长抑制作用。结论本研究表明，选择性考克斯-2抑制剂JTE-522和CDDP联合治疗膀胱癌细胞在体外和体内产生协同细胞毒性和细胞凋亡。这些发现支持了JTE-522和CDDP组合用于治疗膀胱癌的潜在临床应用，作为具有更高选择性细胞毒性和更少副作用的新形式的治疗。
PURPOSE Cyclooxygenase-2 (COX-2) is a key inducible enzyme involved in the production of prostaglandins and its inhibitors have been shown to induce apoptosis in various cancer cells. Several anticancer agents also mediate apoptosis and may share the common intracellular pathways leading to apoptosis with COX-2 inhibitors. We reasoned that combination treatment of bladder cancer cells with COX-2 inhibitors and anticancer agents may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 (4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide) synergizes with anticancer agents in cytotoxicity and apoptosis against bladder cancer cells in vitro and in vivo. MATERIALS AND METHODS Cytotoxicity was determined by the microculture tetrazolium dye assay. RESULTS Combination treatment of T24 bladder cancer cells with JTE-522 and cis-diamminedichloroplatinum (II) (CDDP) resulted in a synergistic cytotoxic effect. Synergy achieved in cytotoxicity with JTE-522 and CDDP was shown to be due to apoptosis. Treatment of T24 cells with JTE-522 decreased expression of the anti-apoptotic molecule Bcl-2. The in vivo significant growth inhibitory effect of JTE-522 and CDDP against the T24 line heterotransplanted in SCID mice was also observed. CONCLUSIONS This study demonstrates that combination treatment of bladder cancer cells with the selective COX-2 inhibitor JTE-522 and CDDP results in synergistic cytotoxicity and apoptosis in vitro and in vivo. These findings support the potential clinical application of a combination of JTE-522 and CDDP for the treatment of bladder cancer as a new form of therapy with more selective cytotoxicity and fewer collateral side effects.