Tolcapone induces oxidative stress leading to apoptosis and inhibition of tumor growth in Neuroblastoma

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. Cancer Medicine Open Access 1342

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism

“…Since this generation of ROS induces cytotoxicity and neurodegeneration, COMT, MAO, and VMAT2 play an important role in preventing dopamine oxidation in dopaminergic neurons [ 38 ]. Therefore, Tolcapone, a potent COMT inhibitor to treat Parkinson’s disease, was reported in neuroblastoma cell lines to induce oxidative stress leading to caspase-3-mediated apoptosis and to inhibit tumor proliferation [ 44 ]. The efficacy of Tolcapone in neuroblastoma cell lines was also demonstrated in the present study and showed synergy effect with VMAT2 inhibitor in MYCN-cluster representative IMR-32 cell line.…”

Systems Pharmacogenomics – Gene, Disease, Drug and Placebo Interactions: A Case Study in COMT

“…Once the crystal structure of COMT was solved, rational design was used to create nitrocatechol inhibitors, such as entacapone and tolcapone, which contain a catechol with a nitro group at position 4 on the benzene ring [94,116]. These drugs are potent reversible inhibitors of COMT, and although their primary clinical application is as an adjunct to levodopa in Parkinson disease, RCTs have explored their effects in attention [117], cognitive deficits in schizophrenia [118], and based on tolcapone's apoptotic effects, as a chemotherapeutic in neuroblastoma [95,119].…”

Differential Interactome Based Drug Repositioning Unraveled Abacavir, Exemestane, Nortriptyline Hydrochloride, and Tolcapone as Potential Therapeutics for Colorectal Cancers

“…Moreover, nortriptyline, a tricyclic antidepressant used to treat depression, however, has antineoplastic activity in various cancers such as bladder, prostate, myeloma ( Pan et al, 2010 ; Mao et al, 2011 ; Yuan et al, 2015 ). In addition, recent studies have shown that tolcapone, a catechol-O-methyltransferase inhibitor used in Parkinson’s disease, decreases cell viability in lung cancer and neuroblastoma cell lines ( Forester and Lambert, 2014 ; Maser et al, 2017 ).…”