南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (6): 905-912.doi: 10.12122/j.issn.1673-4254.2022.06.15

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柴胡桂枝汤加减方联合卡培他滨抑制三阴性乳腺癌裸鼠皮下移植瘤的生长：基于抑制IL-6/STAT3信号通路

方雨潇，王淑美，杨 倩，游松凡，幸享玲   

  1. 重庆医科大学中医药学院//中医药防治代谢性疾病重庆市重点实验室，重庆 400016
  • 出版日期:2022-06-20 发布日期:2022-06-27

Chaihu Guizhi Decoction plus or minus formula combined with capecitabine inhibits IL-6/STAT3 signaling to suppress triple-negative breast cancer xenografts in nude mice

FANG Yuxiao, WANG Shumei, YANG Qian, YOU Songfan, XING Xiangling   

  1. Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
  • Online:2022-06-20 Published:2022-06-27

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摘要： 目的 探讨柴胡桂枝汤加减方（CHGZD）联合卡培他滨对三阴性乳腺癌裸鼠皮下移植瘤生长及凋亡的影响及其作用机制。方法 建立三阴性乳腺癌移植瘤模型，随机分为模型对照（等体积双蒸水）组，CHGZD低（10.62 g/kg/d）、中（21.23 g/kg/d）、高（42.46 g/kg/d）剂量组，卡培他滨（0.2 mg/kg/d）组，联合组（CHGZD 42.46 g/kg/d+卡培他滨0.2 mg/kg/d），10只/组，干预21 d。观察小鼠一般情况，给药结束后测瘤体积、称瘤质量并计算抑瘤率；苏木素-伊红（HE）染色观察肿瘤组织病理学改变；ELISA检测血清中IL-6水平；实时荧光定量聚合酶链式反应、Western blot分别检测各组肿瘤组织中IL-6、STAT3、p-STAT3蛋白水平及肿瘤生长和凋亡相关基因Bax、Bcl-2和CyclinD1的表达。结果 与模型对照组比较，中药组和联合组乳腺癌荷瘤裸鼠摄食量增加，精神状态较好，反应灵敏，体质量增加，瘤体积、瘤质量显著降低（P<0.01）；与卡培他滨组比较，中、高剂量组及联合组抑瘤率显著升高（P<0.01）；与模型对照组比较，中、高剂量组及联合组肿瘤组织出现了不同程度的肿瘤细胞退变，肿瘤细胞密度明显减少；中药组和联合组IL-6水平，IL-6、STAT3 mRNA，IL-6、STAT3和p-STAT3蛋白表达显著降低（P<0.05），其下游基因Bcl-2和CyclinD1 mRNA和蛋白表达显著降低（P<0.05），Bax mRNA和蛋白表达显著升高（P<0.05）。结论 柴胡桂枝汤加减方与卡培他滨联用可显著抑制三阴性乳腺癌裸鼠体内肿瘤的生长，其作用机制可能为抑制IL-6/STAT3信号通路，调控Bax、Bcl-2和CyclinD1基因表达抑制细胞的增殖和分化，诱导细胞凋亡，从而发挥抗肿瘤作用。

关键词: 柴胡桂枝汤加减方；三阴性乳腺癌；IL-6/STAT3信号通路；凋亡

Abstract: Objective To investigate the effect of Chaihu Guizhi Decoction (CHGZD) combined with capecitabine on growth and apoptosis of subcutaneous triple-negative breast cancer xenografts in nude mice and explore the possible mechanism. Methods Nude mouse models bearing subcutaneous triple-negative breast cancer xenografts were randomized into 6 groups (n=10) for treatment with distilled water (model group), low (10.62 g/kg), medium (21.23 g/kg) and high (42.46 g/kg) doses of CHGZD, capecitabine (0.2 mg/kg), or the combination of CHGZD (42.46 g/kg) and capecitabine (0.2 mg/k) once daily for 21 consecutive days. The general condition of mice was observed, and after 21-day treatments, the tumors were dissected for measurement of tumor volume and weight and histopathological examination with HE staining. Serum IL-6 levels of the mice were determined with enzyme-linked immunosorbent assay (ELISA), and the expression levels of IL-6, STAT3, p-STAT3, Bax, Bcl-2 and cyclin D1 in the tumor tissues were detected using real-time PCR and Western blotting. Results Compared with those in the model group, the tumor-bearing mice receiving treatments with CHGZD showed significantly increased food intake with good general condition, sensitive responses, increased body weight, and lower tumor mass (P<0.01). Compared with capecitabine treatment alone, treatment with CHGZD alone at the medium and high doses and the combined treatment all resulted in significantly higher tumor inhibition rates (P<0.01), induced obvious tumor tissue degeneration and reduced the tumor cell density. Treatments with CHGZD, both alone and in combination with capecitabine, significantly decreased serum IL-6 level, lowered the mRNA expression levels of IL-6 and STAT3, the protein expressions of IL-6, STAT3 and P-STAT3 (P<0.05), and the mRNA and protein expressions of Bcl-2 and cyclin D1 (P<0.05), and increased the mRNA and protein expressions of Bax in the tumor tissues (P<0.05). Conclusion CHGZD combined with capecitabine can significantly inhibit tumor growth in nude mice bearing triple-negative breast cancer xenografts, the mechanism of which may involve the inhibition of IL-6/STAT3 signaling pathway and regulation of Bax, Bcl-2 and cyclin D1 expressions to suppress tumor cell proliferation and differentiation and induce cell apoptosis.

Key words: Chaihu Guizhi decoction; triple-negative breast cancer; IL-6/STAT3 signaling pathway; apoptosis