Int J Oncol：川芎嗪靶向COX-2抑制肿瘤转移

环氧化酶(cyclooxygenase,COX)是参与花生四烯酸的环氧酶代谢途径中的限速酶，可催化花生四烯酸转化为前列腺素(prostaglandins，PGs)。近年来研究显示，COX-2在一些肿瘤中存在过度表达现象，提示COX-2可能与肿瘤的发生发展密切相关。

环氧合酶（COX）-2在肺癌中起着重要作用，是肺癌侵袭和转移的关键因素。传统中药川芎有效成分川芎嗪（TMP），历来用于治疗神经、血管和心血管疾病。最近Int J Oncol杂志刊登论文报道TMP对癌症病人有有利的影响。然而，一直以来TMP对肺癌的功能和机制尚未被阐明。

在这项研究中，研究人员探究了在体外和体内，TMP的分子靶点是否是COX-2。结果表明，川芎嗪抑制A549细胞增殖和细胞周期进程，并且具有剂量和时间依赖性。在体外川芎嗪处理A549细胞能显著抑制COX-2和MMP-2/TIMP-2的活性，降低肿瘤细胞侵袭能力。

此外，体内实验显示川芎嗪明显抑制A549转移裸鼠模型的肿瘤的生长，其与降低COX-2的表达有关。这项临床前研究证实COX-2通路抑制剂对人肺腺癌细胞株A549的治疗非常有效，TMP可能成为一种新的抗肿瘤药物，川芎嗪能起到化学预防和治疗非小细胞肺癌。

doi:10.3892/ijo.2012.1375
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Inhibition of cyclooxygenase-2 by tetramethylpyrazine and its effects on A549 cell invasion and metastasis

Chun-Yan Zheng, Wei Xiao, Mao-Xiang Zhu, Xiu-Jie Pan, Zhi-Hua Yang, Sheng-Yu Zhou

Cyclooxygenase (COX)-2 plays an important role in tumorigenesis and has been implicated to be a critical factor for invasion and metastasis of lung cancer. Tetramethylpyrazine (TMP), an effective component of the traditional Chinese medicine Chuanxiong, has been traditionally used in treating neurovascular and cardiovascular diseases. Recently TMP has been reported to have beneficial effect in cancer patients. However, the function and the mechanism of TMP in lung cancer have not been elucidated to date. In this study, we investigated the in vitro and in vivo effect of TMP in tumorigenesis and whether COX-2 is a molecular target of TMP. We showed that TMP exhibited a dose- and time-dependent inhibition on A549 cell proliferation by suppressing cell cycle progression. In vitro treatment of A549 cells with TMP resulted in a significant inhibition of invasion, associated with reduced activities of COX-2 and MMP-2/TIMP-2. Furthermore, in vivo experiments showed that TMP significantly suppressed metastatic growth of A549 cells and COX-2 expression in metastatic nude mouse model. This preclinical study provides the first evidence for the novel anti-tumor effects of TMP as a COX-2 pathway inhibitor in human adenocarcinoma cell line A549. These studies suggest that TMP may serve as an effective agent for the treatment and chemoprevention of non-small cell lung cancer.