Vitexins, nature-derived lignan compounds, induce apoptosis and suppress tumor growth.
Vitexins, nature-derived lignan compounds, induce apoptosis and suppress tumor growth.
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DOI：
10.1158/1078-0432.ccr-09-0661
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发表时间：
2009-08-15
期刊：
影响因子：
--
通讯作者：
Shi YE
中科院分区：
文献类型：
--
作者：
Zhou Y;Liu YE;Cao J;Zeng G;Shen C;Li Y;Zhou M;Chen Y;Pu W;Potters L;Shi YE
亚麻籽中的木脂素如木脂素二葡萄糖苷(SDG)被代谢成生物活性的哺乳动物木脂素End和Enl。由于哺乳动物木脂素的化学结构与天然雌激素相似，因此它们被认为具有选择性雌激素受体调节剂(SERM)的作用，因此具有抗癌作用。我们从中草药黄荆子中分离得到一系列木脂素类化合物，命名为牡荆素。我们纯化了几种牡荆素木脂素化合物。在癌细胞和肿瘤异种移植模型中分析了细胞毒性和抗肿瘤作用。测定了牡荆素在大鼠体内的代谢。与经典木脂素不同，牡荆素不代谢为End和Enl。Vitexin EVN-50和纯化的Vitexin化合物VB1的混合物对乳腺、前列腺和卵巢癌细胞具有细胞毒作用，并通过裂解PARP蛋白、上调Bax表达和下调Bcl2表达来诱导细胞凋亡。这种诱导细胞凋亡的机制似乎是通过激活caspase来实现的，因为抑制caspase活性可以显著减少诱导的细胞凋亡。我们在包括乳腺癌、前列腺癌、肝癌和宫颈癌在内的七种肿瘤异种移植模型上展示了EVN-50的广泛抗肿瘤活性。与体外实验结果一致，EVN-50可诱导移植瘤细胞凋亡，下调Bcl2的表达，上调Bax的表达。牡荆素是一类天然的木脂素类化合物，其作用和抗癌作用是通过不同于经典木脂素的作用机制实现的。牡荆素诱导的抗肿瘤作用和细胞毒活性是通过促凋亡过程发挥的，而促凋亡过程是通过降低Bcl2/Bax比值和激活caspase来实现的。
Lignans such as secoisolariciresinol diglucoside (SDG) in flaxseed, are metabolizes to bioactive mammalian lignans of END and ENL. Because mammalian lignans have chemical structural similarity to the natural estrogen, they are thought to behave like selective estrogen receptor modulators (SERM) and therefore have anticancer effect against hormone-related cancers. We isolated a series of lignan compounds, named as Vitexins, from the seed of Chinese herb Vitex Negundo. We purified several Vitexin lignan compounds. Cytotoxic and antitumor effects were analyzed in cancer cells and in tumor xenograft models. In vivo metabolism of Vitexins was determined in rat. Contrasts to the classical lignans, Vitexins were not metabolized to END and ENL. A mixture of Vitexins EVn-50 and purified Vitexin compound VB1 have cytotoxic effect on breast, prostate, and ovarian cancer cells and induces apoptosis with cleavage in PARP protein, up-regulation of Bax, and down-regulation of Bcl-2. This induction of apoptosis seems to be mediated by activation of caspases because inhibition of caspases activity significantly reduced induced apoptosis. We demonstrated a broad antitumor activity of EVn-50 on seven tumor xenograft models including breast, prostate, liver, and cervical cancers. Consistent with in vitro data, EVn-50 treatment induced apoptosis, down-regulated of Bcl-2, and up-regulated Bax in tumor xenografts. Vitexin is a class of nature lignan compounds, whose action and anticancer effect is mediated by the mechanisms different from the classical lignans. Vitexin induced antitumor effect and cytotoxic activity is exerted through proapoptotic process, which is mediated by a decreased Bcl-2/Bax ratio and activation of caspases.