Inhibition of cyclooxygenase-2 by tetramethylpyrazine and its effects on A549 cell invasion and metastasis

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.