title: Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells.
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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marijke C C
authors.initials: MC
authors.lastname: Sachweh
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: William C
authors.initials: WC
authors.lastname: Stafford
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Drummond
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna R
authors.initials: AR
authors.lastname: McCarthy
authors.affiliation: Centre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Tayside, United Kingdom.
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.affiliation: Centre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Tayside, United Kingdom.
authors.forename: Johanna
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bertha
authors.initials: B
authors.lastname: Brodin
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sonia
authors.initials: S
authors.lastname: Laín
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology*; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D001583:Benzoxazoles; D007093:Imidazoles; D007211:Indoles; C000607113:MJ25 compound; D010879:Piperazines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013450:Sulfones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077484:Vemurafenib; D001310:Auranofin; C482205:nutlin 3; D005980:Glutathione Reductase; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D005978:Glutathione
keywords: auranofin; malignant melanoma; p53; thioredoxin reductase 1; vemurafenib