乳腺癌是最常见的女性恶性肿瘤。虽然目前个体化或分子靶向癌症疗法更受欢迎,但是细胞毒性化疗对于晚期乳腺癌患者仍为可选方案。然而,化疗耐药性仍然是乳腺癌治疗常见和关键的限制因素。 2017年6月5日,澳大利亚《癌症杂志》在线发表中国长春吉林大学、美国纽约哥伦比亚大学的研究报告,发现黄连素(小檗碱)可增强化疗敏感性,并通过剂量调节腺苷一磷酸活化蛋白激酶(AMPK)信号,从而诱导乳腺癌细胞凋亡。 AMPK是一种能被腺苷一磷酸(AMP)激活的丝氨酸蛋白激酶,还可以被上游的一个激酶磷酸化而激活,一旦被激活,可以磷酸化乙酰辅酶A羧化酶、3-羟基-3-甲基戊二酰辅酶A还原酶等靶蛋白,从而影响脂肪酸胆固醇合成、脂肪酸氧化和胰岛素分泌等。已知黄连素为AMPK激活剂,已被发现具有多种活性,包括抗肿瘤作用。 本研究分析了不同剂量的黄连素对体外和体内耐药型人类乳腺癌MCF-7/MDR细胞的化疗敏感作用,以及AMPK活化对多柔比星(阿霉素)化学敏感性的潜在作用机制。 结果发现,黄连素可以通过剂量调节方式克服多柔比星耐药性:一方面,小剂量黄连素可以通过AMPK-缺氧诱导因子1α(HIF-1α)-P糖蛋白(P-gp)通路,增强耐药型乳腺癌细胞对多柔比星的敏感性。另一方面,大剂量黄连素单独通过不依赖HIF-1α表达的AMPK-p53通路,直接诱导乳腺癌细胞凋亡。
因此,黄连素使耐药型乳腺癌对多柔比星化疗敏感,并在体外和体内通过剂量调节AMPK信号通路直接诱导乳腺癌细胞凋亡。黄连素可能是一种有希望用于乳腺癌治疗的化学增敏和化学治疗药物。 相关阅读 J Cancer. 2017 Jun 5;8(9):1679-1689. Berberine Enhances Chemosensitivity and Induces Apoptosis Through Dose-orchestrated AMPK Signaling in Breast Cancer. Pan Y, Zhang F, Zhao Y, Shao D, Zheng X, Chen Y, He K, Li J, Chen L. College of Basic Medical Sciences, Jilin University, Changchun 130021, China; School of Nursing, Jilin University, Changchun 130020, China; Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Breast cancer is the most common malignancy in women. Although personalized or targeting molecular cancer therapy is more popular up to now, the cytotoxicity chemotherapy for patients with advanced breast cancer is considered as the alternative option. However, chemoresistance is still the common and critical limitation for breast cancer treatment. Berberine, known as AMPK activator, has shown multiple activities including antitumor effect. In this study, we investigate the chemosensitive effect of different dosages berberine on drug-resistant human breast cancer MCF-7/MDR cell in vitro and in vivo, and the mechanisms underlying AMPK activation on Doxorubicin (DOX) chemosensitivity. Our results showed that berberine could overcome DOX resistance in dose-orchestrated manner: On one hand, low-dose berberine can enhance DOX sensitivity in drug-resistance breast cancer cells through AMPK-HIF-1α-P-gp pathway. On the other hand, high-dose berberine alone directly induces apoptosis through the AMPK-p53 pathway with the independence of HIF-1α expression. Taken together, our findings demonstrate that berberine sensitizes drug-resistant breast cancer to DOX chemotherapy and directly induces apoptosis through the dose-orchestrated AMPK signaling pathway in vitro and in vivo. Berberine appears to be a promising chemosensitizer and chemotherapeutic drug for breast cancer treatment. Keywords: berberine, breast cancer resistance, AMPK, HIF-1α, p53. DOI: 10.7150/jca.19106 |
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