Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.
Introduction: Macrophage migration inhibitory factor (MIF) plays a pivotal role in inflammatory and immune diseases, and is also implicated in carcinogenesis. This study aimed to determine if serum levels and gastric epithelial MIF expression are associated with gastric precancerous lesions and cancer. Method: Ninety patients (M/F, 54/36, age, 56±16 years), 15 with normal gastric mucosa, 15 with H. pylori-associated chronic antral gastritis, 20 with intestinal metaplasia in the antrum, and 40 with antral adenocarcinoma, were included in this study. Immunohistochemistry was used to determine MIF expression in gastric epithelial cells, and enzyme-linked immunosorbent assay (ELISA) was used to measure serum MIF. Five gastric cancer cell lines (AGS, MKN-45, MKN-28, MGC-803 and SGC-7901) and one non-malignant gastric cell line (GES-1) were cultured for 24 hours. MIF protein in the supernatant was measured by ELISA, and MIF mRNA in cultured cells was determined by reverse transcription-polymerase chain reaction. Results: MIF expression in epithelial cells was weak in normal mucosa (12%), but increased in gastritis (52%), intestinal metaplasia (66%) and gastric cancer (96%) (P<0.001, ANOVA). Serum MIF level was also increased with the pathological changes (576±82 pg/ml in normal mucosa, 2100±349 pg/ml in gastritis, 4498±253 pg/ml in intestinal metaplasia and 9737±1249 pg/ml in gastric cancer, P<0.001, ANOVA). There was a significant correlation between epithelial MIF expression and serum MIF level (R=0.776, P<0.001). Expression of MIF protein and mRNA was increased in all cancer cell lines, compared to the non-malignant cell line. Conclusions: Advanced gastric pathology is associated with a higher MIF expression in epithelial cells. The epithelial MIF expression directly correlated with serum MIF concentrations. Hence MIF plays a role in gastric carcinogenesis and serum MIF levels may be an important biomarker for diagnosis and prognosis.
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