Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells
Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells
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DOI：
10.1093/carcin/bgl030
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发表时间：
2006-08-01
期刊：
影响因子：
4.7
通讯作者：
Katiyar, Santosh K.
中科院分区：
文献类型：
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作者：
Mantena, Sudheer K.;Baliga, Manjeshwar S.;Katiyar, Santosh K.
可用于治疗转移性乳腺癌的策略有限。饮食中的植物性药物对这种疾病可能有更好的保护作用。因此，我们研究了葡萄籽原花青素(GSPs)对高转移小鼠乳腺癌细胞系的影响。体外培养的乳腺癌细胞4T1、MCF-7和MDA-MB-468经GSPs处理后，细胞增殖和活力受到明显抑制，4T1细胞呈时间和剂量依赖性地诱导凋亡。进一步分析表明，Bax/Bcl2蛋白的比例发生了改变，有利于细胞凋亡，而Bax siRNA表达下调可阻断GSPs诱导的4T1细胞的凋亡。诱导细胞凋亡与细胞色素c释放、APAF-1表达增加、caspase3和聚(ADP-核糖)聚合酶激活有关。PAN-caspase抑制剂(Z-VAD-FMK)可部分但显着抑制4T1细胞的凋亡，提示caspase激活依赖和激活非激活途径均参与了GSPs诱导的4T1细胞的凋亡。然后，通过将4T1细胞移植到Balb/c小鼠皮下的体内模型来检验饮食GSP的效果。膳食GSPs(0.2和0.5%，w/w)显著抑制4T1肿瘤细胞的生长，增加肿瘤微环境中bax：bcl2蛋白的比例，细胞色素c的释放，APAF-1的诱导和caspase3的激活。值得注意的是，肿瘤细胞向肺部的转移受到显著抑制，小鼠的存活率提高。这些数据表明，GSPs对乳腺癌具有化疗效果，包括抑制转移。
The strategies available for the treatment of metastatic breast cancer are limited. Dietary botanicals may have a better protective effect on this disease. We therefore investigated the effects of grape seed proanthocyanidins (GSPs) on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of breast cancer cells, 4T1, MCF-7 and MDA-MB-468, with GSPs resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in 4T1 cells in a time- and dose-dependent manner. Further analysis indicated an alteration in the ratio of Bax/Bcl-2 proteins in favor of apoptosis, and the knockdown of Bax using Bax siRNA transfection of 4T1 cells resulted in blocking of GSPs-induced apoptosis. Induction of apoptosis was associated with the release of cytochrome c, increased expression of Apaf-1 and activation of caspase 3 and poly (ADP-ribose) polymerase. Treatment with the pan-caspase inhibitor (Z-VAD-FMK) resulted in partial but significant inhibition of apoptosis in 4T1 cells suggesting the involvement of both caspase activation-dependent and activation-independent pathways in the apoptosis of 4T1 cells induced by GSPs. The effects of dietary GSPs were then examined using an in vivo model in which 4T1 cells were implanted subcutaneously in Balb/c mice. Dietary GSPs (0.2 and 0.5 %, w/w) significantly inhibited the growth of the implanted 4T1 tumor cells and increased the ratio of Bax:Bcl-2 proteins, cytochrome c release, induction of Apaf-1 and activation of caspase 3 in the tumor microenvironment. Notably, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggest that GSPs possess chemotherapeutic efficacy against breast cancer including inhibition of metastasis.