Antioxidants block proteasome inhibitor function in endometrial carcinoma cells.
We have recently demonstrated that proteasome inhibitors can be effective in inducing apoptotic cell death in endometrial carcinoma cell lines and primary culture explants. Increasing evidence suggests that reactive oxygen species are responsible for proteasome inhibitor-induced cell killing. Antioxidants can thus block apoptosis (cell death) triggered by proteasome inhibition. Here, we have evaluated the effects of different antioxidants (edaravone and tiron) on endometrial carcinoma cells treated with aldehyde proteasome inhibitors (MG-132 or ALLN), the boronic acid-based proteasome inhibitor (bortezomib) and the epoxyketone, epoxomicin. We show that tiron specifically inhibited the cytotoxic effects of bortezomib, whereas edaravone inhibited cell death caused by aldehyde-based proteasome inhibitors. We have, however, found that edaravone completely inhibited accumulation of ubiquitin and proteasome activity decrease caused by MG-132 or ALLN, but not by bortezomib. Conversely, tiron inhibited the ubiquitin accumulation and proteasome activity decrease caused by bortezomib. These results suggest that edaravone and tiron rescue cells of proteasome inhibitors from cell death, by inhibiting blockade of proteasome caused by MG-132 and ALLN or bortezomib, respectively. We also tested other antioxidants, and we found that vitamin C inhibited bortezomib-induced cell death. Similar to tiron, vitamin C inhibited cell death by blocking the ability of bortezomib to inhibit the proteasome. Until now, all the antioxidants that blocked proteasome inhibitor-induced cell death also blocked the proteasome inhibitor mechanism of action.
Llobet
David
D
Oncologic Pathology Group, Biomedical Research Institute, Lleida, Spain.
Eritja
Nuria
N
Encinas
Mario
M
Sorolla
Anabel
A
Yeramian
Andree
A
Schoenenberger
Joan Antoni
JA
Llombart-Cussac
Antonio
A
Marti
Rosa M
RM
Matias-Guiu
Xavier
X
Dolcet
Xavier
X
D000975:Antioxidants / Q000494:pharmacology*; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D004880:Ergothioneine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
D000975:Antioxidants; D001897:Boronic Acids; D061945:Caspase Inhibitors; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D025801:Ubiquitin; D014815:Vitamins; C063261:acetylleucyl-leucyl-norleucinal; D014810:Vitamin E; D002083:Butylated Hydroxyanisole; D000069286:Bortezomib; C046582:succinyl-leucyl-leucyl-valyl-tyrosyl-methylcoumarinamide; D004880:Ergothioneine; D053148:Caspase 3; D053453:Caspase 9; D001205:Ascorbic Acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000077553:Edaravone; D000983:Antipyrine; C078846:epoxomicin