Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/Akt pathway.
Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/Akt pathway.
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DOI：
10.1371/journal.pone.0043064
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Katiyar SK
中科院分区：
文献类型：
--
作者：
Prasad R;Vaid M;Katiyar SK
胰腺癌是一种侵袭性恶性肿瘤，诊断时往往已处于晚期，预后较差。在这里，我们报告了使用体外和体内模型评估的葡萄籽生物活性原花青素 (GSP) 的化疗效果。用 GSP 体外处理人胰腺癌细胞（Miapaca-2、PANC-1 和 AsPC-1）会降低细胞活力并增加细胞周期的 G2/M 期停滞，从而以剂量和时间依赖性方式诱导细胞凋亡。 GSPs诱导的胰腺癌细胞凋亡与Bcl-2和Bcl-xl水平的降低以及Bax和活化的caspase-3水平的增加有关。用 GSP 处理 Miapaca-2 和 PANC-1 细胞还降低了磷脂酰肌醇 3 激酶 (PI3K) 的水平和 Akt Ser473 的磷酸化。 siRNA 敲除胰腺癌细胞中的 PI3K 也降低了 Akt 的磷酸化。此外，GSP（0.5%，w/w）作为补充 AIN76A 对照饮食显着抑制无胸腺裸鼠皮下生长的 Miapaca-2 胰腺肿瘤异种移植物的生长，这与：（i）抑制细胞增殖，（ii）诱导肿瘤细胞凋亡，（iii）增加 Bax 表达，减少抗凋亡蛋白表达和 caspase-3 阳性细胞的激活，（iv）减少PI3K 和 p-Akt 在肿瘤异种移植组织中的表达。总之，这些结果表明 GSP 可能对胰腺癌细胞的生长具有潜在的化疗作用。
Pancreatic cancer is an aggressive malignancy that is frequently diagnosed at an advanced stage with poor prognosis. Here, we report the chemotherapeutic effects of bioactive proanthocyanidins from grape seeds (GSPs) as assessed using In Vitro and In Vivo models. Treatment of human pancreatic cancer cells (Miapaca-2, PANC-1 and AsPC-1) with GSPs In Vitro reduced cell viability and increased G2/M phase arrest of the cell cycle leading to induction of apoptosis in a dose- and time-dependent manner. The GSPs-induced apoptosis of pancreatic cancer cells was associated with a decrease in the levels of Bcl-2 and Bcl-xl and an increase in the levels of Bax and activated caspase-3. Treatment of Miapaca-2 and PANC-1 cells with GSPs also decreased the levels of phosphatidylinositol-3-kinase (PI3K) and phosphorylation of Akt at ser473. siRNA knockdown of PI3K from pancreatic cancer cells also reduced the phosphorylation of Akt. Further, dietary administration of GSPs (0.5%, w/w) as a supplemented AIN76A control diet significantly inhibited the growth of Miapaca-2 pancreatic tumor xenografts grown subcutaneously in athymic nude mice, which was associated with: (i) inhibition of cell proliferation, (ii) induction of apoptosis of tumor cells, (iii) increased expression of Bax, reduced expression of anti-apoptotic proteins and activation of caspase-3-positive cells, and (iv) decreased expression of PI3K and p-Akt in tumor xenograft tissues. Together, these results suggest that GSPs may have a potential chemotherapeutic effect on pancreatic cancer cell growth.
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