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.

Hydrogen peroxide – production, fate and role in redox signaling of tumor cells

“…Therefore components of the anti-oxidant processes including the Trx system represent potential therapeutic targets for the treatment of cancer patients to trigger ROS mediated cell death (Table 3 ). This is in line with the reduced tumor cell proliferation, induced apoptosis and increased sensitivity of tumor cells to anti-cancer therapy in the presence of Trx and TrxR1 inhibitors [ 213 , 214 ]. Since a cross-talk between different anti-oxidant molecules has been shown, a combinatorial targeting of these molecules is essential for complete inhibition of the anti-oxidant defense system.…”

Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy inTP53 mutant pancreatic tumors

“…Inhibitors of TrxR are currently under pre-clinical development and are promising candidates for cancer treatment[30]. Several small molecules activating wild-type or mutant p53 were also shown to inhibit TrxR[21,31,32]. The small molecule APR-246, APR-246, a mutant p53-reactivating compound in Phase II clinical development, is a pro-drug, converted in cells to methylene quinuclidinone (MQ) [33].…”

Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer

“…Auranofin is a drug that is approved for the treatment of rheumatoid arthritis. Recently, treatment with AF was discovered to inhibit TrxR and induce ROS in cancer cells, which was associated with high in vitro and in vivo potency of AF against cancer cells [ 11 , 25 ]. With the goal of potential repurposing AF for the treatment of gastric cancer, our preclinical studies presented here demonstrate that AF could induce ROS in the gastric cancer cells.…”