Matrine Inhibits Proliferation and Induces Apoptosis of Pancreatic Cancer Cells in Vitro and in Vivo
Matrine Inhibits Proliferation and Induces Apoptosis of Pancreatic Cancer Cells in Vitro and in Vivo
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苦参碱在体外和体内抑制胰腺癌细胞增殖并诱导其凋亡
DOI：
10.1248/bpb.33.1740
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发表时间：
2010-10-01
影响因子：
2
通讯作者：
Sun, Xueying
中科院分区：
文献类型：
--
作者：
Liu, Tianyou;Song, Yon;Sun, Xueying
苦参碱是从中草药苦参中提取的生物碱，对各种类型的癌细胞表现出抗增殖和促凋亡能力。本研究旨在研究其在体外和体内对人胰腺癌细胞的抗癌活性及其机制。将人BxPC-3和PANC-1胰腺癌细胞以及人HL-7702肝细胞与不同浓度的苦参碱孵育。通过3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四氮唑（MTT）测定法评估细胞活力，并通过流式细胞术评估细胞凋亡。在裸BALB/c小鼠中建立皮下BxPC-3异种移植肿瘤，并且腹膜内（i. p.）管理。监测并收获肿瘤。肿瘤切片用抗Ki-67抗体（Ab）免疫染色以检查细胞增殖，或用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸（dUTP）缺口末端标记（TUNEL）染色以评价原位细胞凋亡。Western blot检测增殖细胞核抗原（PCNA）和多种凋亡相关蛋白在细胞和肿瘤组织中的表达。苦参碱通过下调PCNA的表达抑制细胞活力，通过降低Bcl-2/Bax的比值、上调Fas和增加caspase-8、-3和-9的活化诱导细胞凋亡，并呈剂量依赖性。苦参碱以剂量依赖性方式抑制肿瘤生长，并调节肿瘤基因表达，与体外结果一致。苦参碱对HL-7702细胞的存活率和小鼠体重无明显影响。这些结果表明苦参碱可能是一种潜在的治疗胰腺癌的天然药物。
Matrine, an alkaloid extracted from a Chinese herb, Sophora flavescens AIT., has exhibited anti-proliferative and pro-apoptotic abilities against various types of cancer cells. This study aims to investigate its anti-cancer activity and underlying mechanisms in human pancreatic cancer cells in vitro and in vivo. Human BxPC-3 and PANC-1 pancreatic cancer cells, and human HL-7702 liver cells were incubated with matrine at different concentrations. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell apoptosis, by flow cytometry. Subcutaneous BxPC-3 xenograft tumors were established in nude BALB/c mice, and matrine was intraperitoneally (i.p.) administered. The tumors were monitored and harvested. Tumor sections were immunostained with an anti-Ki-67 antibody (Ab) to examine cell proliferation, or stained with terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) to evaluate in situ cell apoptosis. The expression of proliferating cell nuclear antigen (PCNA) and several apoptosis-related proteins in cells and tumor tissues were evaluated by Western blot analysis. In in vitro assays, matrine inhibited cell viability by downregulating the expression of PCNA, and induced cell apoptosis by reducing the ratio of Bcl-2/Bax, upregulating Fas, and increasing activation of caspases-8,-3 and -9, in a dose-dependent manner. Administration of matrine inhibited tumor growth in a dose-dependent manner, and regulated tumoral gene expression consistent with the in vitro results. But matrine had no significant effects on the viability of HL-7702 cells or the bodyweight of mice compared to controls. These results indicate matrine may be a potential and promising agent of natural resource to treat pancreatic cancer.