Abstract. Cyclooxygenase-2 (COX-2) has a critical role in the invasiveness and metastasis of gastric cancer. In addition, paclitaxel (PTX) and harmine (HM) were reported to be potential therapeutic drug candidates for cancer therapy; however, the synergistic antitumor effect of PTX and HM combined treatment on the human gastric cancer cells remains to be elucidated. The aim of the present study was to evaluate the effects of PTX and/or HM on the cell migration and invasion in two human gastric cancer cell lines, SGC-7901 and MKN-45. MTT assay was used to detect the growth inhibition induced by PTX and HM . The Transwell assay was employed to assess the effects of PTX and HM on the cell migration and invasion. The expression levels of COX-2 and matrix metalloproteinase-9 (MMP-9) were analyzed by western blot analysis. The results demonstrated that PTX and HM inhibited cell proliferation in a dose-dependent manner. Individually PTX and HM were able to inhibit the migration and invasion of two human gastric cancer cells; however, the combination of PTX and HM exerted synergistic effects on migration and invasion inhibition, with downregulation of COX-2 and matrix metalloproteinase (MMP)-9. In conclusion, the results of the present study indicated that combination chemotherapy using PTX with HM exerted an antitumor effect, which may be implicated for the treatment of gastric cancer. Of note, the combination of the two drugs inhibited migration and invasion more effectively compared with each drug alone, the mechanism of which proceeded via the downregulation of COX-2 expression.

Abstract. Cyclooxygenase-2 (COX-2) serves an important role in the carcinogenesis and progression of gastric cancer. Harmine (HM) and paclitaxel (PTX) are reported as promising drug candidates for cancer therapy, but whether a synergistic anti-tumor effect of HM combined with PTX exists in human gastric cancer remains unknown. The present study evaluated the effects of HM and/or PTX on cell proliferation and apoptosis in a gastric cancer cell line, SGC-7901. HM and PTX inhibited cell proliferation in a dose-dependent manner. Both HM and PTX alone induced apoptosis in gastric cancer cells. The combination of HM and PTX exerted synergistic effects on proliferation inhibition and apoptosis induction in SGC-7901 cells, with down-regulation of COX-2, PCNA and Bcl-2 and up-regulation of Bax expression. The results indicated that combination chemotherapy using HM with PTX exerts an anti-tumor effect for treating gastric cancer. The combination of the two drugs inhibits gastric cancer development more effectively than each drug alone through down-regulation of COX-2 expression. IntroductionGastric cancer has been a significant health problem worldwide due to its poor prognosis and increasing incidence (1). According to the latest literature, 800,000 cancer-associated mortalities are caused by gastric cancer each year globally, making it the second leading cause of cancer-associated mortalities in the world (2,3). At present, chemotherapy has become one of the major means for treating gastric cancer of middle and advanced stages (4,5). As a standard anticancer drug, paclitaxel (PTX) serves a significant role in the treatment of a number of tumors. As reported in latest studies, the efficiency of single anticancer drug-paclitaxel reaches 11-23% in treating the gastric cancer of middle and advanced stages, while that of drug combination therapy is 50-60% (6). Harmine (HM), originally isolated from the seeds of Peganum harmala, is a tricyclic compound belonging to the β-carboline alkaloids. It inhibits the proliferation of tumor cells and induces apoptosis, and it performs well in reducing angiogenesis, tumor promotion and mutation (7,8). It has become a new focus in the chemoprevention study about cancer in recent years. Recent studies have demonstrated that HM possessed significant anti-tumor potential both in vitro and in vivo (9,10). However, the synergistic anti-tumor effect of a combination of HM and PTX on human gastric cancer remains unknown.Cyclooxygenase (COX), a key enzyme in the conversion of arachidonic acid to prostaglandins (PGs) and other eicosanoids, exists as two isoforms: Constitutive COX-1 and mitogen-inducible COX-2. COX-2 is also constitutively expressed in gastric cancer and is related to cell proliferation and apoptosis, tumor invasiveness and metastasis (11). Our previous studies have demonstrated that COX-2 inhibition by selective COX-2 inhibitors or small interfering RNA (siRNA) could suppress cell proliferation and induces apoptosis in human gastric cancer cells (12,13). Recently, we demonstrated...