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.
Highlights
Cutaneous malignant melanoma is the most dangerous type of skin cancer and incidence rates have been rising continuously over the past decades [1, 2]
MJ25 (Figure 1a) was identified as an active compound in this screen, displaying modest p53 activation. As it was identified as a thioredoxin reductase 1 (TrxR1) inhibitor with an IC50 of 1.122 μM (PubChem BioAssay number: 588453; http://pubchem.ncbi.nlm.nih.gov), it was selected for further analysis
MJ25 was subsequently repurchased and its activation of p53-dependent transcription confirmed in ARN8 cells as well as in the T22 cell line, a murine prostate-derived cell line stably transfected with the same β-galactosidase reporter gene as ARN8 cells [51]
Summary
Cutaneous malignant melanoma is the most dangerous type of skin cancer and incidence rates have been rising continuously over the past decades [1, 2]. Vemurafenib (Zelboraf, PLX4032) [3] is approved for the treatment of unresectable or metastatic melanoma in which the serine/threonine kinase BRAF has been mutated at Val600, as is the case in approximately 50% of patients [4]. Drug resistance and relapse following treatment with vemurafenib are major problems, and the average tumor-free survival time after treatment has remained less than one year [5]. A number of countries have excluded this drug from subsidy within their health care programs due to a high cost/benefit ratio. Despite promising results being achieved with these agents, lack of responsiveness and relapse are still major problems (reviewed in [12, 13])
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