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Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells.
Arch Pharm Res. 2017 Jun; 40(6):746-759.AP

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.

Authors+Show Affiliations

College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea.College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea.College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea.College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea.College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea.College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea.College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea.College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul, 06911, Republic of Korea. yjchun@cau.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28560500

Citation

Lee, Joo-Eun, et al. "Synergistic Induction of Apoptosis By Combination Treatment With Mesupron and Auranofin in Human Breast Cancer Cells." Archives of Pharmacal Research, vol. 40, no. 6, 2017, pp. 746-759.
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. 2017;40(6):746-759.
Lee, J. E., Kwon, Y. J., Baek, H. S., Ye, D. J., Cho, E., Choi, H. K., Oh, K. S., & Chun, Y. J. (2017). Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells. Archives of Pharmacal Research, 40(6), 746-759. https://doi.org/10.1007/s12272-017-0923-0
Lee JE, et al. Synergistic Induction of Apoptosis By Combination Treatment With Mesupron and Auranofin in Human Breast Cancer Cells. Arch Pharm Res. 2017;40(6):746-759. PubMed PMID: 28560500.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells. AU - Lee,Joo-Eun, AU - Kwon,Yeo-Jung, AU - Baek,Hyoung-Seok, AU - Ye,Dong-Jin, AU - Cho,Eunah, AU - Choi,Hyung-Kyoon, AU - Oh,Kyung-Soo, AU - Chun,Young-Jin, Y1 - 2017/05/31/ PY - 2017/04/08/received PY - 2017/05/26/accepted PY - 2017/6/1/pubmed PY - 2018/1/27/medline PY - 2017/6/1/entrez KW - AIF KW - Apoptosis KW - Auranofin KW - Mesupron KW - ROS KW - Synergism SP - 746 EP - 759 JF - Archives of pharmacal research JO - Arch. Pharm. Res. VL - 40 IS - 6 N2 - 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. SN - 0253-6269 UR - https://www.unboundmedicine.com/medline/citation/28560500/Synergistic_induction_of_apoptosis_by_combination_treatment_with_mesupron_and_auranofin_in_human_breast_cancer_cells_ L2 - https://dx.doi.org/10.1007/s12272-017-0923-0 DB - PRIME DP - Unbound Medicine ER -