title: Synthetic polysulfane derivatives induce cell cycle arrest and apoptotic cell death in human hematopoietic cancer cells.
abstract: Natural polysulfanes including diallyltrisulfide (DATS) and diallyltetrasulfide (DATTS) from garlic possess antimicrobial, chemopreventive and anticancer properties. However these compounds exhibit chemical instability and reduced solubility, which prevents their potential clinical applicability. We synthesized six DATS and DATTS derivatives, based on the polysulfane motif, expected to exhibit improved physical and chemical properties and verified their biological activity on human leukemia cells. We identified four novel cytotoxic compounds (IC50 values: compound 1, 24.96±12.37 μM; compound 2, 22.82±4.20 μM; compound 3, 3.86±1.64 μM and compound 5, 40.62±10.07 μM, compared to DATTS: IC50: 9.33±3.86 μM). These polysulfanes possess excellent differential toxicity, as they did not affect proliferating mononuclear blood cells from healthy donors. We further demonstrated ability of active compounds to induce apoptosis in leukemia cells by analysis of nuclear fragmentation and of cleavage of effector and executioner caspases. Apoptosis was preceded by accumulation of cells in G2/M phase with a pro-metaphase-like nuclear pattern as well as microtubular alterations. Prolonged and persistent arrest of cancer cells in early mitosis by the benzyl derivative identifies this compound as the most stable and effective one for further mechanistic and in vivo studies.
authors.affiliation: Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany; Medical Biochemistry and Molecular Biology, Saarland University, Building 44, D-66424 Homburg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Czepukojc
authors.affiliation: Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany; Laboratoire de Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Baltes
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cerella
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Mareike
authors.initials: M
authors.lastname: Kelkel
authors.affiliation: Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Viswanathan
authors.affiliation: Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Salm
authors.affiliation: Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Burkholz
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, Building 44, D-66424 Homburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Mario
authors.initials: M
authors.lastname: Dicato
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, Building 44, D-66424 Homburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Montenarh
authors.affiliation: Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany. Electronic address: c.jacob@mx.uni-saarland.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Jacob
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: marcdiederich@snu.ac.kr.
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000473:pathology*; D006801:Humans; D013440:Sulfides / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D000498:Allyl Compounds; D013440:Sulfides; C042577:diallyl trisulfide; C431585:diallyl tetrasulfide
keywords: Apoptosis; Cancer; Cell cycle; Polysulfanes; Tubulin