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• W2737578366 abstract "1510 Irofulven (hydroxymethylacylfulvene) is a novel pro-apoptotic antitumor drug currently in clinical development. Irofulven reacts with DNA and proteins and both interactions may contribute to its induction of apoptosis. Previous studies demonstrated that treatment of cancer cells with irofulven elicits redox-mediated responses including (i) transient induction of a key redox-controlling protein, thioredoxin (Trx), (ii) activation of redox-dependent transcription factors NF-κB and AP-1, and (iii) pro-oxidative distortion of the cell redox status. Here we examined whether these effects could reflect functional damage to redox controlling proteins. Covalent binding of irofulven to purified human recombinant Trx was demonstrated using [14C]-labeled drug. The high affinity of irofulven for Trx is indicated by the inability of DTT and glutathione (at 25-fold molar excess over Trx) to reduce the level of irofulven-Trx adducts. Irofulven binding is accompanied by the inhibition of Trx reducing activity (IC50=4.5 μM). The drug also binds to and rapidly inactivates the Trx regenerating enzyme, thioredoxin reductase (TrxR), with an IC50 of 20 μM when drug is added directly to the reaction, while a brief (15 min) preincubation of TrxR with 10 μM irofulven resulted in complete inactivation. Purified glutathione-S-transferase is another redox protein that is adducted to and inactivated by irofulven, although this inhibition was weaker than that of Trx and TrxR (IC50 of 45 μM and 10 μM drug without and with a 1 h pre-incubation, respectively). The effects of irofulven on purified redox proteins were corroborated in prostate tumor LNCaP-Pro5 cells. [14C]-irofulven binds to cellular Trx as demonstrated using 2D PAGE of cytosolic extracts followed by autoradiography and Western blotting. Moreover, irofulven decreased the Trx activity in LNCaP-Pro5 cells (40% inhibition by 3 μM drug), despite a transient increase in Trx protein levels. Intracellular activities of TrxR and GST were also reduced by 3 μM drug (by ∼25 and 50%, respectively). In contrast to tumor cells, normal NCM 460 cells remain non-apoptotic even after prolonged treatment with 10 μM irofulven. These cells exhibit approximately 2-fold higher basal activity of Trx than LNCaP-Pro5 cells. Accordingly, treatment of NCM 460 cells with 10 μM irofulven caused only a transient and modest decrease (20%) in Trx activity and had no inhibitory effect on the activity of TrxR and GST. Collectively, the results suggest that targeting and inactivation of the Trx system and other redox-controlling proteins could be a factor in the cellular effects of irofulven, including the differential responses of tumor and normal cells. (Supported by CA78706, CA80936, and MGI Pharma, Inc)." @default.
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• W2737578366 date "2004-04-01" @default.
• W2737578366 modified "2023-09-23" @default.
• W2737578366 title "Irofulven binding and inactivation of purified and cellular redox-controlling proteins" @default.
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