title: Rhodanese-thioredoxin system and allyl sulfur compounds.
abstract: Sodium 2-propenyl thiosulfate, a water-soluble organo-sulfane sulfur compound isolated from garlic, induces apoptosis in a number of cancer cells. The molecular mechanism of action of sodium 2-propenyl thiosulfate has not been completely clarified. In this work we investigated, by in vivo and in vitro experiments, the effects of this compound on the expression and activity of rhodanese. Rhodanese is a protein belonging to a family of enzymes widely present in all phyla and reputed to play a number of distinct biological roles, such as cyanide detoxification, regeneration of iron-sulfur clusters and metabolism of sulfur sulfane compounds. The cytotoxic effects of sodium 2-propenyl thiosulfate on HuT 78 cells were evaluated by flow cytometry and DNA fragmentation and by monitoring the progressive formation of mobile lipids by NMR spectroscopy. Sodium 2-propenyl thiosulfate was also found to induce inhibition of the sulfurtransferase activity in tumor cells. Interestingly, in vitro experiments using fluorescence spectroscopy, kinetic studies and MS analysis showed that sodium 2-propenyl thiosulfate was able to bind the sulfur-free form of the rhodanese, inhibiting its thiosulfate:cyanide-sulfurtransferase activity by thiolation of the catalytic cysteine. The activity of the enzyme was restored by thioredoxin in a concentration-dependent and time-dependent manner. Our results suggest an important involvement of the essential thioredoxin-thioredoxin reductase system in cancer cell cytotoxicity by organo-sulfane sulfur compounds and highlight the correlation between apoptosis induced by these compounds and the damage to the mitochondrial enzymes involved in the repair of the Fe-S cluster and in the detoxification system.
authors.affiliation: Department of Sciences and Chemical Technologies, University of Rome "Tor Vergata", Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Sabelli
authors.forename: Egidio
authors.initials: E
authors.lastname: Iorio
authors.forename: Angelo
authors.initials: A
authors.lastname: De Martino
authors.forename: Franca
authors.initials: F
authors.lastname: Podo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ricci
authors.forename: Giuditta
authors.initials: G
authors.lastname: Viticchiè
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rotilio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Paci
authors.forename: Sonia
authors.initials: S
authors.lastname: Melino
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002384:Catalysis; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D006868:Hydrolysis; D008055:Lipids / Q000096:biosynthesis; D009682:Magnetic Resonance Spectroscopy; D013050:Spectrometry, Fluorescence; D013463:Sulfuric Acid Esters / Q000494:pharmacology*; D013879:Thioredoxins / Q000378:metabolism*; D013884:Thiosulfate Sulfurtransferase / Q000378:metabolism*
chemical_list: C488464:2-propenyl thiosulfate; D000498:Allyl Compounds; D008055:Lipids; D013463:Sulfuric Acid Esters; D013879:Thioredoxins; D013884:Thiosulfate Sulfurtransferase