Wang Shengpeng, Wang Lu, Shi Zhi, Zhong Zhangfeng, Chen Meiwan, Wang Yitao
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China.
PLoS One. 2014 May 15;9(5):e97512. doi: 10.1371/journal.pone.0097512. eCollection 2014.
Drug resistance is one of the main hurdles for the successful treatment of breast cancer. The synchronous targeting of apoptosis resistance and survival signal transduction pathways may be a promising approach to overcome drug resistance. In this study, we determined that evodiamine (EVO), a major constituent of the Chinese herbal medicine Evodiae Fructus, could induce apoptosis of doxorubicin (DOX)-sensitive MCF-7 and DOX-resistant MCF-7/ADR cells in a caspase-dependent manner, as confirmed by significant increases of cleaved poly(ADP-ribose) polymerase (PARP), caspase-7/9, and caspase activities. Notably, the reversed phenomenon of apoptosis resistance by EVO might be attributed to its ability to inhibit the Ras/MEK/ERK pathway and the expression of inhibitors of apoptosis (IAPs). Furthermore, our results indicated that EVO enhanced the apoptotic action of DOX by inhibiting the Ras/MEK/ERK cascade and the expression of IAPs without inhibiting the expression and activity of P-glycoprotein (P-gp). Taken together, our data indicate that EVO, a natural product, may be useful applied alone or in combination with DOX for the treatment of resistant breast cancer.
耐药性是乳腺癌成功治疗的主要障碍之一。同步靶向凋亡抗性和生存信号转导通路可能是克服耐药性的一种有前景的方法。在本研究中，我们确定吴茱萸碱（EVO），一种中药吴茱萸的主要成分，能够以半胱天冬酶依赖性方式诱导阿霉素（DOX）敏感的MCF-7细胞和DOX耐药的MCF-7/ADR细胞凋亡，这通过裂解的聚（ADP-核糖）聚合酶（PARP）、半胱天冬酶-7/9和半胱天冬酶活性的显著增加得到证实。值得注意的是，EVO对凋亡抗性的逆转现象可能归因于其抑制Ras/MEK/ERK通路和凋亡抑制因子（IAPs）表达的能力。此外，我们的结果表明，EVO通过抑制Ras/MEK/ERK级联反应和IAPs的表达增强了DOX的凋亡作用，而不抑制P-糖蛋白（P-gp）的表达和活性。综上所述，我们的数据表明，天然产物EVO单独应用或与DOX联合应用可能对耐药乳腺癌的治疗有用。
