title: Evidence for targeting thioredoxin reductases with ferrocenyl quinone methides. A possible molecular basis for the antiproliferative effect of hydroxyferrocifens on cancer cells.
abstract: Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (1, FcOH; 2, FcOHTAM) and of their corresponding quinone methides (QMs), 1-QM, and 2-QM, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC50 ≈ 2.5 μM) than the hydroxyferrocifens (IC50 ≈ 15 μM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both 2 and 2-QM inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while 1 and 1-QM were scarcely effective. This difference of behavior was ascribed to the competitive conversion of 1-QM to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of 1 and 2 in cancer cells.
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Padova , via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Citta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Folda
authors.forename: Alberto
authors.initials: A
authors.lastname: Bindoli
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigeon
authors.forename: Siden
authors.initials: S
authors.lastname: Top
authors.forename: Anne
authors.initials: A
authors.lastname: Vessières
authors.forename: Michèle
authors.initials: M
authors.lastname: Salmain
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003538:Cystamine / Q000031:analogs & derivatives / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D045563:Indolequinones / Q000138:chemical synthesis / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D000075163:Metallocenes; D009369:Neoplasms / Q000188:drug therapy; D016566:Organoselenium Compounds / Q000737:chemistry; D051381:Rats; D017279:Selenocysteine / Q000737:chemistry; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D045563:Indolequinones; D000075163:Metallocenes; D016566:Organoselenium Compounds; D017279:Selenocysteine; C068040:quinone methide; C014807:selenocystamine; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione; D003538:Cystamine; C004998:ferrocene