| Aim of the study: Pancreatic cancer has one of the poorest outcomes of all cancers because no effective therapies are available. The therapeutic effect of surgery on pancreatic cancer is not remarkable because of the low diagnosis rate of early stage cancer in China. Chemotherapy gives bad side effects and lower five-year survival rate. And also the radiotherapy can't be employed independently for cancer therapy. Therefore, Chinese traditional herb therapy becomes the research focus on pancreatic cancer treatment. Matrine, an alkaloid extracted from a traditional Chinese herb, Sophora flavescens Ait, has exhibited anti-proliferative and pro-apoptotic abilities against various types of cancer cells including cervical carcinoma, ovary carcinoma, gastric cancer, leukemia, colon cancer, hepatoma, glioblastoma. Previously study has indicated that matrine can regulate the expression of cell cyclin proteins, cyclin dependent kinases and their inhibitors. Matrine reduces the mRNA expression of Cycilin D1 and increases the expression of CKIs (p21, p27, p16) in HepG2 cells. This indicates the matrine regulates the expression of positive and negative factors in the G1 period. They function together to inhibit cell proliferation, initiate cell differentiation, apoptosis and then finally kill the cancer cells. Matrine can induce apoptosis through the FASS pathway. The apoptosis rate increases with the drug dosage. It also can impact on the tumor cell signaling pathway. Some research has shown that matrine can inhibit the telomerase activity of tumor cells which was important for cell immortalization. Up to now, there is no research that reports the martine's anti-tumor effects on pancreatic cancer in vitro and in vivo. This study aims to investigate its anti-cancer activity and the underlying mechanisms in human pancreatic cancer cells.Materials and Methods: Human BxPC-3 and PANC-1 pancreatic cancer cells were cultured in RPMI 1640 and DMEM medium containing 10%FBS, respectively. Cells were incubated with matrine at the concentrations of 0, 0.25 mg/ml, 0.5 mg/ml, 0.75 mg/ml, 1.0 mg/ml, 1.25 mg/ml, 1.5 mg/ml, 1.75 mg/ml, 2.0 mg/ml . The cell viability was assessed by MTT assay and cell apoptosis by flow cytometry through Annexin V- FITC staining. Subcutaneous BxPC-3 xenograft tumors were established in nude BALB/c mice, and matrine was i.p. administered. The tumors were monitored and harvested. Tumor sections were immunostained with an anti-Ki-67 Ab to examine cell proliferation, or stained with TUNEL to evaluate in situ cell apoptosis. The expression of PCNA (proliferating cell nuclear antigen), and several apoptosis-related proteins in cells and in tumor tissues was evaluated by Western blot analysis.Results: In in vitro assays, matrine inhibited cell viability by downregulating expression of PCNA, and induced cell apoptosis by reducing the ratio of Bcl-2/Bax, upregulating Fas, and increasing the activation of caspases-8,-3 and -9, in a dose-dependent manner. Similarly, in mice bearing BxPC-3 xenograft tumors, administration of matrine inhibited tumor growth in a dose-dependent manner, and regulated tumoral gene expression consistent with the in vitro observations.Conclusions: This study demonstrates that matrine is able to inhibit pancreatic cancer in vitro and in vivo. There is no significant side effect. Matrine may be a potential and promising agent of natural resource to treat pancreatic cancer. The anti-tumor mechanisms of matrine include inhibiting cell proliferation, inducing cell apoptosis through different pathways. |
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