Grape proanthocyanidins induce apoptosis by loss of mitochondrial membrane potential of human non-small cell lung cancer cells in vitro and in vivo.
Grape proanthocyanidins induce apoptosis by loss of mitochondrial membrane potential of human non-small cell lung cancer cells in vitro and in vivo.
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DOI：
10.1371/journal.pone.0027444
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发表时间：
2011
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：
Singh T;Sharma SD;Katiyar SK
肺癌仍然是世界范围内癌症相关死亡的主要原因，非小细胞肺癌（NSCLC）占肺癌病例总数的约80%。使用无毒的膳食植物化学物质可以被认为是NSCLC管理的化疗策略。在这里，我们报告了葡萄籽原花色素（GSPs）在体外诱导非小细胞肺癌细胞A549和H1299的细胞凋亡，这是通过增加促凋亡蛋白Bax的表达、减少抗凋亡蛋白Bcl 2和Bcl-xl的表达、破坏线粒体膜电位以及激活半胱天冬酶9、3和聚（ADP-核糖）聚合酶（PARP）介导的。用caspase-3抑制剂（z-DEVD-fetamine）预处理A549和H1299细胞显著阻断了这些细胞的GSPs诱导的凋亡，证实了GSPs诱导的凋亡是通过激活caspase-3介导的。用GSPs处理A549和H1299细胞导致G1期阻滞增加。已知细胞周期的G 0/G1期由细胞周期蛋白依赖性激酶（Cdk）、细胞周期蛋白依赖性激酶抑制剂（Cdki）和细胞周期蛋白控制。我们的蛋白质印迹分析表明，GSPs诱导的G1期细胞周期阻滞介导的Cdki蛋白（Cip 1/p21和Kip 1/p27）的表达增加，并在Cdk 2，Cdk 4，Cdk 6和细胞周期蛋白的水平同时下降。此外，经口灌胃给予50、100或200 mg GSP/kg体重的小鼠（5天/周）显著抑制s.c. A549和H1299肺肿瘤裸鼠移植瘤的凋亡诱导、Bax表达增加、抗凋亡蛋白表达减少和caspase-3活化。根据动物实验数据，计算出了人的GSPs等效剂量，该剂量似乎是可负担的和可实现的。总之，这些结果表明，GSPs可能代表一种潜在的治疗剂的非小细胞肺癌。
Lung cancer remains the leading cause of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) represents approximately 80% of total lung cancer cases. The use of non-toxic dietary phytochemicals can be considered as a chemotherapeutic strategy for the management of the NSCLC. Here, we report that grape seed proanthocyanidins (GSPs) induce apoptosis of NSCLC cells, A549 and H1299, in vitro which is mediated through increased expression of pro-apoptotic protein Bax, decreased expression of anti-apoptotic proteins Bcl2 and Bcl-xl, disruption of mitochondrial membrane potential, and activation of caspases 9, 3 and poly (ADP-ribose) polymerase (PARP). Pre-treatment of A549 and H1299 cells with the caspase-3 inhibitor (z-DEVD-fmk) significantly blocked the GSPs-induced apoptosis of these cells confirmed that GSPs-induced apoptosis is mediated through activation of caspases-3. Treatments of A549 and H1299 cells with GSPs resulted in an increase in G1 arrest. G0/G1 phase of the cell cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin-dependent kinase inhibitors (Cdki) and cyclins. Our western blot analyses showed that GSPs-induced G1 cell cycle arrest was mediated through the increased expression of Cdki proteins (Cip1/p21 and Kip1/p27), and a simultaneous decrease in the levels of Cdk2, Cdk4, Cdk6 and cyclins. Further, administration of 50, 100 or 200 mg GSPs/kg body weight of mice by oral gavage (5 d/week) markedly inhibited the growth of s.c. A549 and H1299 lung tumor xenografts in athymic nude mice, which was associated with the induction of apoptotic cell death, increased expression of Bax, reduced expression of anti-apoptotic proteins and activation of caspase-3 in tumor xenograft cells. Based on the data obtained in animal study, human equivalent dose of GSPs was calculated, which seems affordable and attainable. Together, these results suggest that GSPs may represent a potential therapeutic agent for the non-small cell lung cancer.
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影响因子：
4.7
作者：
Mantena, Sudheer K.;Baliga, Manjeshwar S.;Katiyar, Santosh K.
通讯作者：
Katiyar, Santosh K.
影响因子：
5.3
作者：
Ferrigno, D;Buccheri, G
通讯作者：
Buccheri, G
影响因子：
11.5
作者：
Akhtar, Suhail;Meeran, Syed M.;Katiyar, Santosh K.
通讯作者：
Katiyar, Santosh K.
影响因子：
5.8
作者：
BARRY, MA;BEHNKE, CA;EASTMAN, A
通讯作者：
EASTMAN, A
影响因子：
254.7
作者：
Jemal, A;Murray, T;Thun, MJ
通讯作者：
Thun, MJ