title: A scent of therapy: Synthetic polysulfanes with improved physico-chemical properties induce apoptosis in human cancer cells.
abstract: Diallyl sulfanes derived from edible plants are highly potent compounds which at sub-millimolar concentrations are able to induce the formation of reactive oxygen species (ROS) in a variety of different cells, where they often cause an altered redox status. The loss of cellular thiols and/or formation of ROS subsequently triggers a range of cellular responses, including the induction of apoptosis. A great disadvantage of natural diallyl mono- and polysulfanes, however, is their inherent insolubility in water and the extremely bad odour which limits their practical use in humans. Here, we present the synthesis and biological evaluation of two new, especially designed polysulfanes, namely the trisulfide 1-Allyl-3-(2-ethoxyethyl)trisulfide (ATSEE) and the tetrasulfide Allyl-4-benzyltetrasulfide (ATTSB), which are nearly odourless. Both compounds produce O2•- radicals in HCT116 cells and both induce an oxidative defence signalling. Cell viability is especially reduced by the tetrasulfane ATTSB, with an arrest of the cell cycle in the G2-phase. In contrast, the trisulfane ATSEE does not inhibit the cell cycle. In agreement with these findings, treatment of HCT116 cells with ATTSB ultimately results in apoptosis whereas only limited induction of apoptosis has been detected for cells treated with ATSEE. We further show that antioxidative defence mechanisms and death response signalling run in parallel and the dominant pathway decides the fate of the cell. Thus, our results not only illuminate the intricate mode of action of certain polysulfanes; they also demonstrate that the new odourless tri- and tetrasulfanes exhibit a similar activity compared to their natural counterparts, yet are easier to handle and also deprived of the offensive odour which so far has prevented most practical applications of such polysulfanes, at least in the context of medicine.
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, D-66424 Homburg, Germany.
authors.forename: Dany Rezk
authors.initials: DR
authors.lastname: Allah
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, D-66424 Homburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schwind
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, D-66424 Homburg, Germany.
authors.forename: Imad Abu
authors.initials: IA
authors.lastname: Asali
authors.affiliation: Bioorganic Chemistry, Department of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany.
authors.forename: Jawad
authors.initials: J
authors.lastname: Nasim
authors.affiliation: Bioorganic Chemistry, Department of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Jacob
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, D-66424 Homburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Götz
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, D-66424 Homburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Montenarh
mesh_terms: D000498:Allyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C000607509:1-allyl-3-(2-ethoxyethyl)trisulfide; D000498:Allyl Compounds; D000975:Antioxidants; D013440:Sulfides; C000607510:allyl-4-benzyltetrasulfide; D011065:Poly(ADP-ribose) Polymerases