Triphala inhibits both in vitro and in vivo xenograft growth of pancreatic tumor cells by inducing apoptosis.
Triphala inhibits both in vitro and in vivo xenograft growth of pancreatic tumor cells by inducing apoptosis.
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Triphala通过诱导凋亡抑制胰腺肿瘤细胞的体外和体内异种移植生长。
DOI：
10.1186/1471-2407-8-294
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发表时间：
2008-10-10
期刊：
影响因子：
3.8
通讯作者：
Srivastava, Sanjay K.
中科院分区：
文献类型：
--
作者：
Shi, Yan;Sahu, Ravi P.;Srivastava, Sanjay K.
Triphala通常用于阿育吠陀医学治疗各种疾病;然而，其作用机制尚未探索。本研究在细胞和体内模型中阐明了Triphala抗人胰腺癌的分子机制。通过Sulphoradamine-B测定法评价Triphala在Capan-2、BxPC-3和HPDE-6细胞中的生长抑制作用。细胞凋亡测定采用细胞死亡实验和蛋白质印迹法。将Triphala经口给予植入Capan-2异种移植物的裸鼠。通过免疫组织化学和蛋白质印迹分析肿瘤。Capan-2细胞暴露于Triphala水提物24 h后，细胞存活率显著下降，呈剂量依赖性，IC 50约为50 μg/ml。Triphala介导的细胞存活率降低与细胞凋亡诱导相关，细胞凋亡诱导与活性氧（ROS）产生相关。在Capan-2细胞中，Triphala诱导的凋亡与p53 Ser-15和ERK Thr-202/Tyr-204的磷酸化有关。当细胞被抗氧化剂N-乙酰半胱氨酸（NAC）预处理时，上述作用被显著阻断，表明ROS的产生参与其中。用p53或MEK-1/2的特异性抑制剂pifithrin-α或U 0126预处理细胞，显著减弱Triphala诱导的细胞凋亡。此外，NAC或U 0126预处理显著减弱Triphala诱导的p53转录活性。类似地，Triphala通过激活ERK诱导另一种胰腺癌细胞系BxPC-3的凋亡。另一方面，Triphala未能诱导正常人胰腺导管上皮细胞（HPDE-6）凋亡或激活ERK或p53。此外，每周5天口服给予PBS中的50 mg/kg或100 mg/kg Triphala显著抑制Capan-2胰腺肿瘤异种移植物的生长。Triphala喂养小鼠中肿瘤生长减少是由于肿瘤细胞凋亡增加，这与p53和ERK活化增加有关。我们的临床前研究表明，Triphala在细胞和体内模型中都能有效抑制人胰腺癌细胞的生长。我们的数据还表明，Triphala的生长抑制作用是由ERK和p53的激活介导的，并显示出治疗和/或预防人胰腺癌的潜力。
Triphala is commonly used in Ayurvedic medicine to treat variety of diseases; however its mechanism of action remains unexplored. This study elucidates the molecular mechanism of Triphala against human pancreatic cancer in the cellular and in vivo model. Growth-inhibitory effects of Triphala were evaluated in Capan-2, BxPC-3 and HPDE-6 cells by Sulphoradamine-B assay. Apoptosis was determined by cell death assay and western blotting. Triphala was administered orally to nude mice implanted with Capan-2 xenograft. Tumors were analyzed by immunohistochemistry and western blotting. Exposure of Capan-2 cells to the aqueous extract of Triphala for 24 h resulted in the significant decrease in the survival of cells in a dose-dependent manner with an IC50 of about 50 μg/ml. Triphala-mediated reduced cell survival correlated with induction of apoptosis, which was associated with reactive oxygen species (ROS) generation. Triphala-induced apoptosis was linked with phosphorylation of p53 at Ser-15 and ERK at Thr-202/Tyr-204 in Capan-2 cells. Above mentioned effects were significantly blocked when the cells were pretreated with an antioxidant N-acetylcysteine (NAC), suggesting the involvement of ROS generation. Pretreatment of cells with pifithrin-α or U0126, specific inhibitors of p53 or MEK-1/2, significantly attenuated Triphala-induced apoptosis. Moreover, NAC or U0126 pretreatment significantly attenuated Triphala-induced p53 transcriptional activity. Similarly, Triphala induced apoptosis in another pancreatic cancer cell line BxPC-3 by activating ERK. On the other hand, Triphala failed to induce apoptosis or activate ERK or p53 in normal human pancreatic ductal epithelial (HPDE-6) cells. Further, oral administration of 50 mg/kg or 100 mg/kg Triphala in PBS, 5 days/week significantly suppressed the growth of Capan-2 pancreatic tumor-xenograft. Reduced tumor-growth in Triphala fed mice was due to increased apoptosis in the tumors cells, which was associated with increased activation of p53 and ERK. Our preclinical studies demonstrate that Triphala is effective in inhibiting the growth of human pancreatic cancer cells in both cellular and in vivo model. Our data also suggests that the growth inhibitory effects of Triphala is mediated by the activation of ERK and p53 and shows potential for the treatment and/or prevention of human pancreatic cancer.
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DOI：
10.1073/pnas.021282898
发表时间：
2001-01-30
影响因子：
11.1
作者：
Gottifredi, V;Shieh, SY;Prives, C
通讯作者：
Prives, C
影响因子：
4.8
作者：
Höcker, M;Rosenberg, I;Wang, TC
通讯作者：
Wang, TC
DOI：
10.1073/pnas.0804226105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Chen, Qi;Espey, Michael Graham;Levine, Mark
通讯作者：
Levine, Mark
影响因子：
4.5
作者：
Lin, T.;Mak, N. K.;Yang, M. S.
通讯作者：
Yang, M. S.
影响因子：
7.9
作者：
Jagetia, GC;Baliga, MS;Kamath, MS
通讯作者：
Kamath, MS