Oncotarget

Research Papers:

Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells

Marijke C.C. Sachweh _, William C. Stafford, Catherine J. Drummond, Anna R. McCarthy, Maureen Higgins, Johanna Campbell, Bertha Brodin, Elias S.J. Arnér and Sonia Laín

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Oncotarget. 2015; 6:16488-16506. https://doi.org/10.18632/oncotarget.4108

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Abstract

Marijke C.C. Sachweh1,*, William C. Stafford2,*, Catherine J. Drummond1, Anna R. McCarthy1, Maureen Higgins3, Johanna Campbell3, Bertha Brodin4, Elias S.J. Arnér2 and Sonia Laín1

1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

2 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

3 Centre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Tayside, United Kingdom

4 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden

* These authors have contributed equally to this work

Correspondence to:

Marijke C.C. Sachweh, email:

Keywords: malignant melanoma, auranofin, vemurafenib, thioredoxin reductase 1, p53

Received: December 15, 2014 Accepted: April 23, 2015 Published: May 12, 2015

Abstract

Malignant melanoma is the most dangerous type of skin cancer. Although recent progress in treatment has been achieved, lack of response, drug resistance and relapse remain major problems. The tumor suppressor p53 is rarely mutated in melanoma, yet it is inactive in the majority of cases due to dysregulation of upstream pathways. Thus, we screened for compounds that can activate p53 in melanoma cells. Here we describe effects of the small molecule MJ25 (2-{[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]thio}-1,3-benzoxazole), which increased the level of p53-dependent transactivation both as a single agent and in combination with nutlin-3. Furthermore, MJ25 showed potent cytotoxicity towards melanoma cell lines, whilst having weaker effects against human normal cells. MJ25 was also identified in an independent screen as an inhibitor of thioredoxin reductase 1 (TrxR1), an important selenoenzyme in the control of oxidative stress and redox regulation. The well-characterized TrxR inhibitor auranofin, which is FDA-approved and currently in clinical trials against leukemia and a number of solid cancers, displayed effects comparable with MJ25 on cells and led to eradication of cultured melanoma cells at low micromolar concentrations. In conclusion, auranofin, MJ25 or other inhibitors of TrxR1 should be evaluated as candidate compounds or leads for targeted therapy of malignant melanoma.


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