Flavokawain A, a novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice
Flavokawain A, a novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice
复制标题
DOI：
10.1158/0008-5472.can-04-3803
复制
发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Simoneau, AR
中科院分区：
文献类型：
--
作者：
Zi, XL;Simoneau, AR
据报道，传统卡瓦制剂的消费与斐济、瓦努阿图和西萨摩亚这三个饮用卡瓦国家的癌症发病率低且不寻常的性别比例（女性比男性多）相关。我们已经鉴定出卡瓦提取物中的黄酮卡瓦因 A、B 和 C，但不是主要的卡瓦内酯卡瓦因，对人类膀胱癌细胞具有强烈的抗增殖和凋亡作用。在侵袭性膀胱癌细胞系 T24 中，黄卡因 A 会导致线粒体膜电位显着丧失，并将细胞色素 c 释放到胞浆中。黄素卡因 A 的这些作用伴随着 Bcl-xL 的时间依赖性减少、Bcl-x(L) 与 Bax 的结合减少以及 Bax 蛋白活性形式的增加。使用原代小鼠胚胎成纤维细胞 Bax 敲除和野生型细胞以及源自 Ku70 Bax 结合域的 Bax 抑制肽，我们发现 Bax 蛋白至少部分是黄素卡因 A 的凋亡作用所必需的。此外，黄卡素 A 下调 X 连锁凋亡抑制剂和生存素的表达。由于 X 连锁凋亡抑制剂和生存素都是细胞凋亡抵抗的主要因素，并且在膀胱肿瘤中过度表达，因此我们的数据表明，黄素卡因 A 可能在膀胱肿瘤中优先诱导细胞凋亡方面具有双重功效。最后，黄卡因 A 的抗癌作用在裸鼠模型（抑制率为 57%）和软琼脂中对膀胱肿瘤细胞的生长抑制中表现得很明显。
Consumption of the traditional kava preparation was reported to correlate with low and uncustomary gender ratios (more cancer in women than men) of cancer incidences in three kava-drinking countries: Fiji, Vanuatu, and Western Samoa. We have identified flavokawain A, B, and C but not the major kavalactone, kawain, in kava extracts as causing strong antiproliferative and apoptotic effect in human bladder cancer cells. Flavokawain A results in a significant loss of mitochondrial membrane potential and release of cytochrome c into the cytosol in an invasive bladder cancer cell line T24. These effects of flavokawain A are accompanied by a time-dependent decrease in Bcl-xL, a decrease in the association of Bcl-x(L), to Bax, and an increase in the active form of Bax protein. Using the primary mouse embryo fibroblasts Bax knockout and wild-type cells as well as a Bax inhibitor peptide derived from the Bax-binding domain of Ku70, we showed that Bax protein was, at least in part, required for the apoptotic effect of flavokawain A. In addition, flavokawain A down-regulates the expression of X-linked inhibitor of apoptosis and survivin. Because both X-linked inhibitor of apoptosis and survivin are main factors for apoptosis resistance and are overexpressed in bladder tumors, our data suggest that flavokawain A may have a dual efficacy in induction of apoptosis preferentially in bladder tumors. Finally, the anticarcinogenic effect of flavokawain A was evident in its inhibitory growth of bladder tumor cells in a nude mice model (57% of inhibition) and in soft agar.