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Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells

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Abstract

Urokinase-type plasminogen activator (uPA) has been validated as a predictive or prognostic biomarker protein, and mesupron is considered the first-in-class anticancer agent to inhibit uPA activity in human breast cancer. In the present study, we showed that the synergism between mesupron and auranofin, a thioredoxin reductase inhibitor, for inducing of apoptosis in MCF-7 human breast cancer cells. Our results demonstrated that mesupron and auranofin significantly lead to inhibition of the cancer cells proliferation; cell cycle arrest at the G1/S phase of the cell cycle, and apoptosis as indicated by caspase 3 activation, poly(ADP-ribose) polymerase cleavage, and annexin V staining. Isobologram analyses of MCF-7 cells showed a clear synergism between mesupron and auranofin. This combined treatment decreased the levels of mitochondrial anti-apoptotic factors, such as BCL-2, BCL-xL, and MCL-1 and caused nuclear translocation of apoptosis-inducing factor. Mitochondrial membrane potential (Δψ m ) was found to be strongly disrupted in combination-treated cells. In addition, combination treatment significantly enhanced the overproduction of reactive oxygen species, which was rescued by N-acetylcysteine treatment. The combination treatment suppressed phosphorylation of Akt, thus contributing to apoptosis. Taken together, our data suggest that the use of mesupron in combination with auranofin may be important in achieving high anticancer synergy.

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Acknowledgements

This research was supported by the Chung-Ang University Graduate Research Scholarship in 2017 and the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (NRF-2015R1A5A1008958).

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  1. College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea

    Joo-Eun Lee, Yeo-Jung Kwon, Hyoung-Seok Baek, Dong-Jin Ye, Eunah Cho, Hyung-Kyoon Choi, Kyung-Soo Oh & Young-Jin Chun

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  1. Joo-Eun Lee
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Lee, JE., Kwon, YJ., Baek, HS. et al. Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells. Arch. Pharm. Res. 40, 746–759 (2017). https://doi.org/10.1007/s12272-017-0923-0

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