Ryu Yeon-Sang, Shin Sangyun, An Hong-Gyu, Kwon Tae-Uk, Baek Hyoung-Seok, Kwon Yeo-Jung, Chun Young-Jin
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
Biomol Ther (Seoul). 2020 Sep 1;28(5):473-481. doi: 10.4062/biomolther.2020.051.
Axl receptor tyrosine kinase has been implicated in cancer progression, invasion, and metastasis in various cancer types. Axl overexpression has been observed in many cancers, and selective inhibitors of Axl, including R428, may be promising therapeutic agents for several human cancers, such as breast, lung, and pancreatic cancers. Here, we examined the cell growth inhibition mediated by R428 and auranofin individually as well as in combination in the human breast cancer cell lines MCF-7 and MDAMB- 231 to identify new advanced combination treatments for human breast cancer. Our data showed that combination therapy with R428 and auranofin markedly inhibited cancer cell proliferation. Isobologram analyses of these cells indicated a clear synergism between R428 and auranofin with a combination index value of 0.73. The combination treatment promoted apoptosis as indicated by caspase 3 activation and poly (ADP-ribose) polymerase cleavage. Cancer cell migration was also significantly inhibited by this combination treatment. Moreover, we found that combination therapy significantly increased the expression level of Bax, a mitochondrial proapoptotic factor, but decreased that of the X-linked inhibitor of apoptosis protein. Furthermore, the suppression of cell viability and induction of Bax expression by the combination treatment were recovered by treatment with N-acetylcysteine. In conclusion, our data demonstrated that combined treatment with R428 and auranofin synergistically induced apoptosis in human breast cancer cells and may thus serve as a novel and valuable approach for cancer therapy.
Axl受体酪氨酸激酶与多种癌症类型的癌症进展、侵袭和转移有关。在许多癌症中都观察到Axl过表达，包括R428在内的Axl选择性抑制剂可能是几种人类癌症（如乳腺癌、肺癌和胰腺癌）的有前景的治疗药物。在这里，我们研究了R428和金诺芬单独以及联合对人乳腺癌细胞系MCF-7和MDAMB-231介导的细胞生长抑制作用，以确定新的先进的人乳腺癌联合治疗方法。我们的数据表明，R428和金诺芬联合治疗显著抑制癌细胞增殖。对这些细胞的等效线图分析表明，R428和金诺芬之间存在明显的协同作用，联合指数值为0.73。联合治疗促进了凋亡，这表现为半胱天冬酶3激活和聚（ADP-核糖）聚合酶裂解。这种联合治疗也显著抑制了癌细胞迁移。此外，我们发现联合治疗显著增加了线粒体促凋亡因子Bax的表达水平，但降低了凋亡蛋白X连锁抑制剂的表达水平。此外，联合治疗对细胞活力的抑制和Bax表达的诱导可通过用N-乙酰半胱氨酸处理来恢复。总之，我们的数据表明，R428和金诺芬联合治疗可协同诱导人乳腺癌细胞凋亡，因此可能是一种新的有价值的癌症治疗方法。
