Abstract
Catechol‐O‐methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O‐methylation. Tolcapone, a drug commonly used in the treatment of Parkinson's disease, is a potent inhibitor of COMT and previous studies indicate that Tolcapone increases the bioavailability of dopamine in cells. In this study, we demonstrate that Tolcapone kills neuroblastoma (NB) cells in preclinical models by inhibition of COMT. Treating four established NB cells lines (SMS‐KCNR, SH‐SY5Y, BE(2)‐C, CHLA‐90) and two primary NB cell lines with Tolcapone for 48 h decreased cell viability in a dose‐dependent manner, with IncuCyte imaging and Western blotting indicating that cell death was due to caspase‐3‐mediated apoptosis. Tolcapone also increased ROS while simultaneously decreasing ATP‐per‐cell in NB cells. Additionally, COMT was inhibited by siRNA in NB cells and showed similar increases in apoptotic markers compared to Tolcapone. In vivo xenograft models displayed inhibition of tumor growth and a significant decrease in time‐to‐event in mice treated with Tolcapone compared to untreated mice. These results indicate that Tolcapone is cytotoxic to neuroblastoma cells and invite further studies into Tolcapone as a promising novel therapy for the treatment of neuroblastoma.
Highlights
Neuroblastoma (NB) is a tumor of the autonomic nervous system originating from the adrenal medulla and autonomic ganglia in the chest and abdomen [1]
Cell viability analysis indicated that Tolcapone is cytotoxic to NB cells with IC50 values ranging from 32.27 μmol/L for SMS-K CNR cells to 219.8 μmol/L for MGT9-102-08 primary cells (Fig. 2A)
The comparison of data obtained from the cell viability and BrdU assays shows that most cell lines had similar IC50 and GI50 values when treated with the same doses of Tolcapone (Fig. 2A and B)
Summary
Neuroblastoma (NB) is a tumor of the autonomic nervous system originating from the adrenal medulla and autonomic ganglia in the chest and abdomen [1]. After leukemia and brain tumors, NB is the third most frequent malignant tumor in children. NB accounts for 15% of all pediatric cancer deaths [2]. About 50% of high-risk patients have relapsed or refractory NB and will succumb to their disease. There are currently no known cures for patients with relapsed or refractory neuroblastoma, with a 5-year survival of
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