Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.051
Synergistic Induction of Apoptosis by the Combination of an Axl Inhibitor and Auranofin in Human Breast Cancer Cells
Yeon-Sang Ryu, Sangyun Shin, Hong-Gyu An, Tae-Uk Kwon, Hyoung-Seok Baek, Yeo-Jung Kwon and Young-Jin Chun*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
*E-mail: yjchun@cau.ac.kr
Tel: +82-2-820-5616, Fax: +82-2-825-5616
The first two authors contributed equally to this study.
Received: April 3, 2020; Revised: May 14, 2020; Accepted: June 1, 2020; Published online: June 15, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
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.
Keywords: Axl receptor tyrosine kinase, Auranofin, Bax, Synergism


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