Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan.
J Agric Food Chem. 2010 Mar 24;58(6):3356-65. doi: 10.1021/jf903793p.
Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death of men in the United States. To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer to more invasive forms. In this study, we identified Saussurea involucrata Kar. et Kir., a rare traditional Chinese medicinal herb, as a potential agent for androgen-independent prostate cancer patients and investigated its biological mechanism as an antineoplastic agent. S. involucrata caused a concentration- and time-dependent inhibition of cell proliferation in human hormone-resistant prostate cancer PC-3 cells. Moreover, in vitro studies in a panel of several types of human cancer cell lines revealed that S. involucrata inhibited cell proliferation with high potency. To evaluate the bioactive compounds, we successively extracted the S. involucrata with fractions of methanol (SI-1), ethyl acetate (SI-2), n-butanol (SI-3), and water (SI-4). Among these extracts, SI-2 contains the most effective bioactivity. SI-2 treatment resulted in significant time-dependent growth inhibition together with G1 phase cell cycle arrest and apoptosis in PC3 cells. In addition, SI-2 treatment strongly induced p21WAF1/CIP and p27KIP1 expression, independent of the p53 pathway, and downregulated expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4). SI-2 treatment increased levels of Bax, cytochrome c, activated caspase-3, and active caspase-9 and decreased Bcl-2 expression level. One of the major targets for the therapy in prostate cancer can be epidermal growth factor receptor (EGFR). SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3. Moreover, p.o. administration of SI-2 induced a dose-dependent inhibition of PC-3 tumor growth in vivo. In summary, our study identifies S. involucrata as an effective inhibitor of EGFR signaling in human hormone-resistant prostate cancer PC-3 cells. We suggest that S. involucrata could be developed as an agent for the management of EGFR-positive human cancers.
前列腺癌是美国男性最常见的恶性肿瘤和第二大死亡原因。迄今为止，尚无有效的治疗方法可以阻止前列腺癌向更具侵袭性的形式发展。在这项研究中，我们发现雪莲，一种罕见的中药，可能是雄激素非依赖性前列腺癌患者的潜在治疗药物，并研究了其作为抗肿瘤药物的生物学机制。雪莲在体外对人激素抵抗性前列腺癌细胞 PC-3 表现出浓度和时间依赖性的抑制细胞增殖作用。此外，在一系列人癌细胞系的体外研究中发现，雪莲具有高效抑制细胞增殖的作用。为了评估雪莲的生物活性成分，我们用甲醇（SI-1）、乙酸乙酯（SI-2）、正丁醇（SI-3）和水（SI-4）对雪莲进行了连续提取。在这些提取物中，SI-2 含有最有效的生物活性。SI-2 处理导致 PC3 细胞的生长抑制呈时间依赖性，并伴有 G1 期细胞周期阻滞和凋亡。此外，SI-2 处理强烈诱导 p21WAF1/CIP 和 p27KIP1 的表达，这与 p53 途径无关，并下调 cyclin D1 和细胞周期蛋白依赖性激酶 4（CDK4）的表达。SI-2 处理增加了 Bax、细胞色素 c、活化的 caspase-3 和活性 caspase-9 的水平，并降低了 Bcl-2 的表达水平。表皮生长因子受体（EGFR）是前列腺癌治疗的一个主要靶点。SI-2 显著降低了 EGFR 的磷酸化水平，并抑制了 AKT 和 STAT3 的激活。此外，SI-2 的口服给药在体内诱导了 PC-3 肿瘤生长的剂量依赖性抑制。综上所述，我们的研究确定雪莲是一种有效的人激素抵抗性前列腺癌细胞 EGFR 信号抑制剂。我们认为雪莲可以开发为治疗 EGFR 阳性人类癌症的药物。
