Reclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention
Reclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention
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DOI：
10.1002/ijc.11710
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发表时间：
2004-04-10
影响因子：
6.4
通讯作者：
Procopio, A
中科院分区：
文献类型：
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作者：
Catalano, A;Graciotti, L;Procopio, A
恶性间皮瘤（MM）仍然是最致命的胸膜，腹膜和心包癌。在这里，我们描述了非甾体抗炎药（NSAID）在体外和体内实验MM模型的影响。与原代正常间皮瘤细胞不同，选择性环氧合酶（考克斯）-2抑制剂塞来昔布可降低来自既往未经治疗的MM患者的几种MM细胞的体外增殖。此外，塞来昔布显著抑制MM细胞在软琼脂中的集落形成（5 × 10 ~（-5）M时为63-78%; p ≤ 0.05），具有显著的抗肿瘤活性，导致>37%的腹腔内MM荷瘤裸鼠长期存活。塞来昔布抑制MM细胞生长比乙酰水杨酸（10（-6）M-10（-2）M）更有效吲哚美辛（10（-6）M-10（-2）M）和考克斯-2抑制剂NS-398（10（-6）M-10（-4）M）这些不同化合物的功效与MM细胞上存在的考克斯-2蛋白水平的量无关。塞来昔布以剂量和时间依赖性方式诱导MM细胞凋亡，其涉及Akt磷酸化减少，Bcl-2和Survivin蛋白表达丢失以及caspase-3激活。此外，血管内皮生长因子（VEGF），MM自分泌生长因子和Akt诱导剂，挽救塞来昔布诱导的细胞凋亡和Akt去磷酸化。当VEGF受体（KDR/Flk-1）抑制剂SU-1498与塞来昔布联合使用时，塞来昔布的体外IC 50降低高达65%。这些数据表明，塞来昔布在MM中可能具有抗肿瘤特性，并为塞来昔布与选择性VEGF抑制剂联合治疗提供了理论依据。(C)2004 Wiley-Liss，Inc.
Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 X 10(-5) M; p less than or equal to 0.05) and it elicited remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM. Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10(-6) M-10(-2) M), indometacin (10(-6) M-10(-2) M) and the COX-2 inhibitor NS-398 (10(-6) M-10(-4) M) Efficacy of these different compounds was not related to the amount of COX-2 protein levels present on MM cells. Celecoxib, in a dose- and time-dependent manner, induced MM cell apoptosis, which involved decreased Akt phosphorylation, loss of Bcl-2 and Survivin protein expression and caspase-3 activation. Furthermore, vascular endothelial growth factor (VEGF), an MM autocrine growth factor and Akt inducer, rescued celecoxib-induced apoptosis and Akt dephosphorylation. When the VEGF receptor (KDR/Flk-1) inhibitor, SU-1498, was used in combination with celecoxib, IC50 of celecoxib in vitro was reduced up to 65%. These data demonstrate that celecoxib may have antitumor properties in MM and provide a rationale for the therapeutic use of celecoxib in combination with a selective VEGF inhibitor. (C) 2004 Wiley-Liss, Inc.