ABSTRACT

Auranofin is a gold complex used as an anti-rheumatic agent and may act as a potent anticancer drug against breast tumors. Trametinib is a specific mitogen-activated protein kinase inhibitor, approved for the treatment of metastatic melanoma. The aim of this study was to examine the synergistic effects of auranofin and trametinib on apoptosis in MCF-7 human breast cancer cells. The combination treatment inhibited cancer cell proliferation and induced cell cycle arrest at the sub-G1 phase and apoptosis via poly (ADP-ribose) polymerase cleavage and caspase-3/7 activation. It is noteworthy that this treatment significantly increased p38 mitogen-activated protein kinase (MAPK) phosphorylation to induce mitochondrial stress, subsequently promoting cancer cell apoptosis through release of apoptosis-inducing factor. Further data demonstrated that combined treatment significantly induced increase in nuclear translocation of AIF. These results indicated that activation of the p38 MAPK signaling pathway and mitochondrial apoptosis may contribute to the synergistic consequences in MCF-7 cells. Collectively, our data demonstrated that combined treatment with auranofin and trametinib exhibited synergistic breast cancer cell death and this combination might be utilized as a novel therapeutic strategy for breast cancer.

摘要

金诺芬是一种金复合物，用作抗风湿药，可以作为有效的抗乳癌药物。曲美替尼是一种特定的促分裂原活化蛋白激酶抑制剂，已被批准用于治疗转移性黑色素瘤。这项研究的目的是检查金诺芬和曲美替尼对MCF-7人乳腺癌细胞凋亡的协同作用。联合治疗抑制癌细胞增殖，并通过聚（ADP-核糖）聚合酶裂解和caspase-3 / 7激活诱导细胞周期停留在亚G1期和凋亡。值得注意的是，这种治疗显着增加了p38丝裂原活化蛋白激酶（MAPK）的磷酸化，从而诱导线粒体应激，随后通过释放凋亡诱导因子来促进癌细胞凋亡。进一步的数据表明，联合治疗显着诱导了AIF核易位的增加。这些结果表明p38 MAPK信号通路的激活和线粒体凋亡可能有助于MCF-7细胞的协同作用。总体而言，我们的数据表明，金诺芬和曲美替尼的联合治疗表现出协同的乳腺癌细胞死亡，这种联合可作为乳腺癌的新型治疗策略。