Peterson G, Barnes S
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.
Cell Growth Differ. 1996 Oct;7(10):1345-51.
Genistein is a naturally occurring dietary protein tyrosine kinase (PTK) inhibitor that is hypothesized to be responsible for the lower rate of breast cancer observed in Asian women consuming soy. Although genistein is a potent in vitro PTK inhibitor, its mechanism of action in vivo is not known. In vivo, breast cancer growth is regulated by estrogens and peptide growth factors, such as epidermal growth factor (EGF), the receptor of which has intrinsic PTK activity. Therefore, genistein may block mammary epithelial cell growth by interfering with signal transduction events stimulated by estradiol or growth factors. The effect of genistein, related isoflavones, and other tyrosine kinase inhibitors on fetal bovine serum-, estradiol-, and EGF-stimulated cell growth and signal transduction pathways was examined in five human breast cancer cell lines. Genistein inhibited the growth of these cells by each of the growth stimuli with IC50 values ranging from 2.6 to over 20 micrograms/ml. Growth inhibition by genistein was cytostatic and reversible at IC50 concentrations. Related isoflavones were less potent growth inhibitors than genistein, whereas the synthetic PTK inhibitor tyrphostin A25 was an equally potent growth inhibitor. The mechanism of genistein growth inhibition in human breast cancer cells did not depend on the presence of functional estrogen receptor signaling pathways or on inhibition of EGF-receptor PTK activity. Furthermore, genistein (< or = 20 micrograms/ml) did not decrease constitutive or EGF-induced tyrosine phosphorylation as determined by Western blotting with antiphosphotyrosine antibodies. These data suggest that although genistein inhibits the growth of breast cancer cells in culture, it does so without gross inhibition of PTK activity.
染料木黄酮是一种天然存在的膳食蛋白质酪氨酸激酶（PTK）抑制剂，据推测，它是食用大豆的亚洲女性乳腺癌发病率较低的原因。尽管染料木黄酮在体外是一种有效的PTK抑制剂，但其体内作用机制尚不清楚。在体内，乳腺癌的生长受雌激素和肽生长因子调节，如表皮生长因子（EGF），其受体具有内在的PTK活性。因此，染料木黄酮可能通过干扰雌二醇或生长因子刺激的信号转导事件来阻断乳腺上皮细胞的生长。在五种人乳腺癌细胞系中检测了染料木黄酮、相关异黄酮和其他酪氨酸激酶抑制剂对胎牛血清、雌二醇和EGF刺激的细胞生长及信号转导途径的影响。染料木黄酮通过每种生长刺激物抑制这些细胞的生长，IC50值范围为2.6至超过20微克/毫升。在IC50浓度下，染料木黄酮引起的生长抑制是细胞周期停滞性的且可逆。相关异黄酮作为生长抑制剂的效力低于染料木黄酮，而合成PTK抑制剂 tyrphostin A25是一种效力相当的生长抑制剂。染料木黄酮抑制人乳腺癌细胞生长的机制不依赖于功能性雌激素受体信号通路的存在，也不依赖于对EGF受体PTK活性的抑制。此外，如用抗磷酸酪氨酸抗体进行蛋白质印迹法所测定，染料木黄酮（≤20微克/毫升）不会降低组成性或EGF诱导的酪氨酸磷酸化。这些数据表明，尽管染料木黄酮在培养中抑制乳腺癌细胞的生长，但其抑制方式并非对PTK活性的全面抑制。
