文章摘要

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

作者: 1王红鲜, 1林秋生, 2吉坤美, 3郭芬芬, 1陈天文, 1胡璟, 1孔恒, 2蔡泽浪
1 广东医科大学附属深圳南山医院 甲乳外科，广东 深圳 518052
2 深圳大学 医学部，广东 深圳 518060
3 中山大学实验动物中心，广东 广州 510080
通讯: 王红鲜 Email: hnsmx001@yeah.net
DOI: 10.3978/.10.3978/j.issn.1005-6947.10.3978/j.issn.1005-6947.2017.08.007
基金: 广东省医学科研基金资助项目, A2014664

摘要

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。
关键词： 乳腺肿瘤 抗药性 肿瘤 槲皮素 异种移植模型抗肿瘤试验

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

Authors: 1WANG Hongxian, 1LIN Qiusheng, 2JI Kunmei, 3GUO Fenfen, 1CHEN Tianwen, 1HU Jing, 1KONG Heng, 2CAI Zelang
1 Department of Thyroid and breast Surgery, Affiliated Nanshan Hospital, Guangdong Medical University, Shenzhen, Guangdong 518052, China
2 Health Science Center, Shenzhen University, Shenzhen, Guangdong 518060, China
3 Laboratory Animal Center, Sun Yat-Sen University, Guangzhou 510080, China

CorrespondingAuthor:WANG Hongxian Email: hnsmx001@yeah.net

Abstract

Objective: To investigate the enhancing effect of quercetin (QUE) 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 (QUE 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 (QUE+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 ERα, 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 QUE+TAM group and QUE 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 QUE+TAM group (P<0.05), but showed no significant difference in the other two groups (both P>0.05); the ERα protein expression was increased while HER-2, pMAPK and pAkt protein expressions were decreased markedly in the tumor tissues of QUE+TAM group and QUE 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: QUE 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 ERα expression; QUE has potential toxicity and adverse activities, so its safe dose range and minimum effective dose should be determined.
Keywords： Breast Neoplasms Drug Resistance Neoplasm Quercetin Xenograft Model Antitumor Assays