槲皮素对内分泌耐药乳腺癌三苯氧胺治疗增敏作用的体内研究

Enhancing effect of quercetin on sensitivity of endocrine-resistant breast cancer to tamoxifen therapy:an in vivo study

目的:探讨槲皮素(QUE)对内分泌耐药乳腺癌三苯氧胺(TAM)治疗的增敏作用。方法:用大剂量TAM冲击法构建TAM耐药乳腺癌细胞株MCF-7/TAM-R并移植裸鼠后,将荷瘤鼠随机分为4组,分别给予溶媒(对照组)、QUE 50 mg/kg 1次/2 d(QUE组)、TAM 5 mg/kg 1次/d(TAM组)、QUE 50 mg/kg 1次/2 d+TAM 5 mg/kg 1次/d(QUE+TAM组)处理,动态观测各组荷瘤鼠的一般情况与瘤体体积的变化,于给药21 d后,处死各组荷瘤鼠,检测瘤体质量及瘤组织ERα、HER-2、pMAPK、MAPK、pAkt、Akt蛋白的表达。结果:给药过程中,QUE+TAM组和QUE组裸鼠摄食减少、体质量减轻,对照组与TAM组裸鼠无明显异常;至第12天开始,QUE+TAM组瘤体生长呈下降趋势,且第21天明显下降(P<0.05),其余各组瘤体均呈持续增长。与对照组比较,QUE+TAM组瘤体质量明显减轻(P<0.05),而其余两组均无统计学差异(均P>0.05);QUE+TAM组和QUE组瘤组织中ERα蛋白高表达,HER-2、pMAPK、pAkt蛋白低表达,而TAM组上述蛋白表达均无明显差异,各组非磷酸化的MAPK、Akt蛋白表达均无明显差异。结论:QUE能恢复内分泌耐药乳腺癌对TAM的敏感性,可能与其下调HER-2及其下游信号pMAPK、pAkt的表达,并上调ERα的表达有关;QUE有潜在的毒副作用,其安全范围及有效剂量有待进一步探讨。

Objective： To investigate the enhancing effect of quercetin （Q.UE） on sensitivity of endocrine-resistant breast cancer to tamoxifen （TAM） therapy. Methods： The TAM-resistant breast cancer cell lines （MCF-7/TAM-R） were induced by high dose TAM pulse exposure, and then were transplanted into nude mice. After that, the tumor xenograft-bearing nude mice were randomly divided into 4 groups, and were administrated with vehicles （control group）, QUE 50 mg/kg once every 2 days （Q.UE group）, TAM 5 mg/kg once daily （TAM group） or QUE 50 mg/kg once every 2 days plus TAM 5 mg/kg once per day （Q.UE＋TAM group）, respectively. The general conditions of the tumor-bearing mice and the volume changes of the tumors were monitored, and the mice in each group were sacrificed at 21th day after treatment, and then the tumor weight and the expressions of ERa, HER-2, pMAPK, MAPK, pAkt and Akt in the tumor tissue were determined. Results： During treatment, the daily food intake and body weight were significantly reduced in mice of Q UE＋TAM group and Q.UE group, but showed no abnormalities in mice of control group and TAM group; the tumor growth started to decrease from the 12th day, and decreased significantly to the 21th day in QUE＋TAM group （P〈0.05）, while the tumors grew continuously in other groups. Compared with control group, the tumor weight was significantly decreased in Q UE＋TAM group （P〈0.05）, but showed no significant difference in the other two groups （both P〉0.05）; the ERa protein expression was increased while HER-2, pMAPK and pAkt protein expressions were decreased markedly in the tumor tissues of Q.UE＋TAM group and Q.UE group, but the expressions of all above proteins showed no obvious change in TAM control, while the expressions of unphosphorylated MAPK and Akt showed no remarkable changes in any of the groups. Conclusion： Q UE can restore the sensitivity of endocrine-resistant breast cancer to TAM, which may probably be associated with its down-regulating HER-2 and downstream pMAPK and pAkt expressions, and up-regulating ERa expression; Q UE has potential toxicity and adverse activities, so its safe dose range and minimum effective dose should be determined.