Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells
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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.
KeywordsAuranofin Mesupron Apoptosis Synergism ROS AIF
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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Conflict of interest
The authors declare that there are no conflicts of interest.
- Chen X, Shi X, Zhao C, Li X, Lan X, Liu S, Huang H, Liu N, Liao S, Zang D, Song W, Liu Q, Carter BZ, Dou QP, Wang X, Liu J (2014) Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms. Oncotarget 5:9118–9132CrossRefPubMedPubMedCentralGoogle Scholar
- Fiskus W, Saba N, Shen M, Ghias M, Liu J, Gupta SD, Chauhan L, Rao R, Gunewardena S, Schorno K, Austin CP, Maddocks K, Byrd J, Melnick A, Huang P, Wiestner A, Bhalla KN (2014) Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Res 74:2520–2532CrossRefPubMedPubMedCentralGoogle Scholar
- Frederickson M, Callaghan O, Chessari G, Congreve M, Cowan SR, Matthews JE, Mcmenamin R, Smith DM, Vinkovic M, Wallis NG (2008) Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator. J Med Chem 51:183–186CrossRefPubMedGoogle Scholar
- Harbeck N, Kates RE, Schmitt M (2002) Clinical relevance of invasion factors urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 for individualized therapy decisions in primary breast cancer is greatest when used in combination. J Clin Oncol 20:1000–1007CrossRefPubMedGoogle Scholar
- Harbeck N, Schmitt M, Meisner C, Friedel C, Untch M, Schmidt M, Sweep CG, Lisboa BW, Lux MP, Beck T, Hasmuller S, Kiechle M, Janicke F, Thomssen C (2013) Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients. Eur J Cancer 49:1825–1835CrossRefPubMedGoogle Scholar
- Jelisavac-Cosic S, Sirotkovic-Skerlev M, Kulic A, Jakic-Razumovic J, Kovac Z, Vrbanec D (2011) Prognostic significance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in patients with primary invasive ductal breast carcinoma—a 7.5-year follow-up study. Tumori 97:532–539PubMedGoogle Scholar
- Liu N, Li X, Huang H, Zhao C, Liao S, Yang C, Liu S, Song W, Lu X, Lan X, Chen X, Yi S, Xu L, Jiang L, Dong X, Zhou P, Li S, Wang S, Shi X, Dou PQ, Wang X, Liu J (2014) Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth. Oncotarget 5:5453–5471CrossRefPubMedPubMedCentralGoogle Scholar
- Rackham O, Shearwood AM, Thyer R, Mcnamara E, Davies SM, Callus BA, Miranda-Vizuete A, Berners-Price SJ, Cheng Q, Arner ES, Filipovska A (2011) Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: implications for development of specific inhibitors. Free Radic Biol Med 50:689–699CrossRefPubMedGoogle Scholar
- Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova NL, Buhrmann C, Shakibaei M, Boland CR, Goel A (2015) Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis 36:355–367CrossRefPubMedPubMedCentralGoogle Scholar
- Zou P, Chen M, Ji J, Chen W, Chen X, Ying S, Zhang J, Zhang Z, Liu Z, Yang S, Liang G (2015) Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer. Oncotarget 6:36505–36521PubMedPubMedCentralGoogle Scholar