Molecular mechanisms of growth inhibition on human tongue cancer SCC-4 cells by berberine：in vitro and in vivo

• Main Authors: Yung-Tsuan Ho, 何永鑽
• Other Authors: Tsai-chung Li
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/58287981675249200971

博士 === 中國醫藥大學 === 中國醫學研究所博士班 === 97 === 1. Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells Phytochemicals have been recognized to have potential chemo-preventive or chemotherapeutic efficacy in cancer treatment. Here, we hypothesized that berberine would have anti-cancer activities in human tongue cancer SCC-4 cells. Results indicated that berberine decreased the viability of SCC-4 cells which was initiated by the generation of reactive oxygen species, via an increase in cytosolic Ca2+. Berberine induced apoptosis was associated with a reduction of the mitochondrial membrane potential associated with changes in the Bax/Bcl-2 ratio, release of cytochrome c from mitochondria and activation of down-stream caspase-3. Real time PCR showed that berberine stimulated gene expression of caspase-8, -9 and -3, apoptosis-inducing factor (AIF) and Endo G. The present study demonstrated that berberine-mediated apoptosis of SCC-4 cells is regulated by ROS, mitochondria, caspase-3 -dependent and -independent pathways, suggesting that berberine may be considered for future studies as a promising therapeutic candidate for human tongue cancer. 2. Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9 There is increasing evidence that urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) play an important role in cancer metastasis and angiogenesis. Inhibition of uPA and MMPs could suppress migration and invasion of cancer cells. Berberine, one of the main constituents of the plant Rhizoma coptidis, is a type of isoquinoline alkaloid, reported to have anticancer effects in different human cancer cell lines. There is however, no available information on effects of berberine on migration and invasion of human tongue cancer cells. Here, we report that berberine inhibited migration and invasion of human SCC-4 tongue squamous carcinoma cells. This action was mediated by the p-JNK, p-ERK, p-38, IκK and NF-κB signaling pathways resulting in inhibition of MMP-2 and -9 in human SCC-4 tongue squamous carcinoma cells. These results suggest that berberine down-regulates uPA , MMP-2 and -9 expressions in SCC-4 cells through the NF-κB and MAPK mediated pathway and a novel function of berberine is to inhibit the invasive capacity of malignant cells. 3. Berberine Inhibits Human Tongue Squamous Carcinoma Cancer Tumor Growth in a Murine Xenograft Model Many evidences have been shown that dietary fruits and vegetables can act as protective for maligancies and carcinogenesis. Berberine is one of component from natural plant such as barberry. Many studies have been shown that berberine induced cell cycle arrest and apoptosis in many cancer cell lines. Our primary studies also showed that berberine induced apoptosis in human tongue cancer SCC-4 cells in vitro. But there is no report to show berberine inhibited SCC-4 cancer cells in vivo on a murine xenograft animal model. SCC-4 tumor cells were implanted into mice and groups of mice were treated with vehicle, berberine (10 mg/kg ) and doxorubicin (4 mg/kg ). The tested agents were injected once per four days intraperitoneally, with treatment starting 4 weeks prior to cell inoculation. Treatment with 4 mg/kg of doxorubicin or with 10 mg/kg of berberine resulted in a reduction in tumor incidence. Tumor size in xenograft mice treated with 10 mg/kg berberine was significantly smaller than that in the control group. Our findings indicate that berbeirne inhibits tumor growth in a xenograft animal model, berberine may represent a tongue cancer preventive agent.