Cancer Prevention Research Program, Palindrome Liaisons, Montvale, NJ 07645-1559, USA.
Mol Med Rep. 2012 Jan;5(1):22-8. doi: 10.3892/mmr.2011.617. Epub 2011 Oct 4.
Selective estrogen receptor modulators and a combination of mechanistically distinct chemotherapeutic agents represent conventional therapeutic interventions for estrogen receptor-positive (ER+) clinical breast cancer. Long-term treatment with these agents is associated with acquired tumor resistance and other adverse side effects that impact on patient compliance. Herbal medicines are being widely used in complementary and alternative medicine. However, long-term safety and efficacy of the use of herbal medicines, as well as their interaction with conventional endocrine and chemotherapeutic drug regimens remain largely unknown. The present study utilized a human cell culture model for ER+ clinical breast cancer to examine the potential therapeutic efficacy of an aqueous extract prepared from the fruit of popular Chinese herb Cornus officinalis (CO), also known as Fructus cornii. The human mammary carcinoma-derived MCF-7 cell line represented the model. Status of anchorage-independent growth and cellular metabolism of 17β-estradiol (E₂) represented the quantitative end-point biomarkers for efficacy. MCF-7 cells adapted for growth in serum-depleted medium (0.7% serum, <1 nM E₂) retained their endocrine responsiveness as evidenced by growth promotion by physiological levels of E₂, and growth inhibition by the selective ER modulator tamoxifen at the clinically achievable concentrations. Treatment of MCF-7 cells with CO resulted in inhibition of E₂-stimulated growth in a dose-dependent manner. Similarly, CO treatment also produced a dose-dependent progressive reduction in the number of anchorage-independent colonies, indicating effective reduction of the carcinogenic risk. Treatment of MCF-7 cells with CO at a maximally effective cytostatic concentration resulted in a 5.1-fold increase in the formation of the anti-prolifertive E₂ metabolite 2-hydoxyestrone (2-OHE₁), a 63.6% decrease in the formation of the pro-mitogenic metabolite 16α-hydroxestrone (16-αOHE₁) and a 9.1% decrease in the formation of mitogenically inert metabolite estrone (E₃). These alterations led to a 14.5-fold increase in the 2-OHE₁:16α-OHE₁, and a 3.3-fold increase in the E₃:16α-OHE1 ratios. These data validate a rapid cell culture-based mechanistic approach to prioritize efficacious herbal medicinal products for long-term animal studies and future clinical trials on ER+ clinical breast cancer.
选择性雌激素受体调节剂和机制不同的化疗药物的联合治疗是雌激素受体阳性（ER+）临床乳腺癌的常规治疗干预措施。这些药物的长期治疗与获得性肿瘤耐药性和其他不良反应有关，这些不良反应会影响患者的依从性。草药在补充和替代医学中被广泛应用。然而，草药的长期安全性和疗效，以及它们与传统内分泌和化疗药物方案的相互作用在很大程度上仍然未知。本研究利用 ER+临床乳腺癌的人细胞培养模型，研究了从中国常用草药山茱萸（CO）果实中提取的水提物对乳腺癌的潜在治疗效果，该草药也被称为山茱萸。人乳腺腺癌衍生的 MCF-7 细胞系作为模型。锚定非依赖性生长和 17β-雌二醇（E₂）的细胞代谢状态作为功效的定量终点生物标志物。适应在血清耗尽培养基（0.7%血清，<1 nM E₂）中生长的 MCF-7 细胞保持其内分泌反应性，表现为生理水平的 E₂促进生长，以及临床可达到浓度的选择性雌激素受体调节剂他莫昔芬抑制生长。CO 处理 MCF-7 细胞呈剂量依赖性抑制 E₂刺激的生长。同样，CO 处理也呈剂量依赖性逐渐减少锚定非依赖性集落的数量，表明有效降低了致癌风险。在最大细胞毒性浓度下用 CO 处理 MCF-7 细胞可使抗增殖性 E₂代谢物 2-羟雌酮（2-OHE₁）的形成增加 5.1 倍，使促有丝分裂代谢物 16α-羟雌酮（16-αOHE₁）的形成减少 63.6%，使有丝分裂惰性代谢物雌酮（E₃）的形成减少 9.1%。这些变化导致 2-OHE₁：16α-OHE₁ 增加 14.5 倍，E₃：16α-OHE1 增加 3.3 倍。这些数据验证了一种快速的基于细胞培养的机制方法，用于优先对 ER+临床乳腺癌进行长期动物研究和未来临床试验的有效草药产品。
