Luteolin inhibits progestin-dependent angiogenesis, stem cell-like characteristics, and growth of human breast cancer xenografts.
Luteolin inhibits progestin-dependent angiogenesis, stem cell-like characteristics, and growth of human breast cancer xenografts.
复制标题
DOI：
10.1186/s40064-015-1242-x
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Hyder SM
中科院分区：
文献类型：
--
作者：
Cook MT;Liang Y;Besch-Williford C;Goyette S;Mafuvadze B;Hyder SM
临床试验和流行病学证据表明，联合雌激素/黄体酮激素替代疗法，而不是单独雌激素治疗，会增加绝经后妇女患乳腺癌的风险。以前我们已经证明天然和合成黄体酮，包括广泛使用的合成黄体酮醋酸甲羟黄体酮（MPA），增加了人类乳腺癌细胞中一种有效的血管生成因子，血管内皮生长因子（VEGF）的产生，这可能为黄体酮的作用机制提供了解释。在这里，我们测试了木犀草素（luteolin，一种常见于水果和蔬菜中的类黄酮）对抑制人乳腺癌细胞中孕激素依赖性VEGF诱导和血管生成、抑制干细胞样特征以及乳腺癌细胞异种移植肿瘤在体内生长和血管生成标志物表达的影响。T47-D和BT-474细胞的活力采用磺胺嘧啶B法测定。采用酶联免疫吸附法监测乳腺癌细胞中VEGF的分泌。采用黄体酮依赖的异种移植肿瘤生长来测定LU在体内的作用。采用CD31免疫组化方法测定异种移植肿瘤的血管密度。CD44表达、醛脱氢酶活性和乳腺球形成测定用于监测乳腺癌细胞的干细胞样特征。木犀草素治疗降低了乳腺癌细胞活力、乳腺癌细胞中依赖孕激素的VEGF分泌，以及裸鼠体内依赖mpa的人乳腺癌细胞异种移植肿瘤的生长。LU治疗还能降低异种移植物肿瘤VEGF表达和血管密度。此外，LU阻断了mpa诱导的乳腺癌细胞获得干细胞样特性。木犀草素有效地阻断了依赖孕激素的人乳腺癌肿瘤生长和人乳腺癌细胞的干细胞样表型。
Clinical trials and epidemiological evidence have shown that combined estrogen/progestin hormone replacement therapy, but not estrogen therapy alone, increases breast cancer risk in post-menopausal women. Previously we have shown that natural and synthetic progestins, including the widely used synthetic progestin medroxyprogesterone acetate (MPA), increase production of a potent angiogenic factor, vascular endothelial growth factor (VEGF), in human breast cancer cells, potentially providing an explanation for progestin’s mechanism of action. Here, we tested the effects of luteolin (LU), a flavonoid commonly found in fruits and vegetables, on inhibiting progestin-dependent VEGF induction and angiogenesis in human breast cancer cells, inhibiting stem cell-like characteristics, as well as breast cancer cell xenograft tumor growth in vivo and expression of angiogenesis markers. Viability of both T47-D and BT-474 cells was measured using sulforhodamine B assays. Enzyme-linked immunosorbent assays were used to monitor VEGF secretion from breast cancer cells. Progestin-dependent xenograft tumor growth was used to determine LU effects in vivo. CD31 immunohistochemistry was used to determine blood-vessel density in xenograft tumors. CD44 expression, aldehyde dehydrogenase activity, and mammosphere-formation assays were used to monitor stem cell-like characteristics of breast cancer cells. Luteolin treatment reduced breast cancer cell viability, progestin-dependent VEGF secretion from breast cancer cells, and growth of MPA-dependent human breast cancer cell xenograft tumors in nude mice. LU treatment also decreased xenograft tumor VEGF expression and blood-vessel density. Furthermore, LU blocked MPA-induced acquisition of stem cell-like properties by breast cancer cells. Luteolin effectively blocks progestin-dependent human breast cancer tumor growth and the stem cell-like phenotype in human breast cancer cells.