Cell cycle arrest in early mitosis and induction of caspase-dependent apoptosis in U937 cells by diallyltetrasulfide (Al2S4).
Naturally occurring organic sulfur compounds (OSCs), such as linear allylsulfides from Allium species, are attracting attention in cancer research, since several OSCs were shown to act beneficially both in chemoprevention and in chemotherapy, while hardly exerting any harmful side effects. Hence, we investigated the possible role of different OSCs in the treatment of leukemia. Thereby, we found that the compounds tested in this study induced apoptosis in U937 cells, with an efficiency depending on the number of sulfides, and selected the most promising candidate, diallyltetrasulfide (Al2S4), for detailed mechanistic studies. Here we show that Al2S4 induced an accumulation of cells in early mitosis (G2/M phase), followed by the activation of caspase-dependent apoptosis. The compound counteracted different anti-apoptotic Bcl-2 family members (Bcl-xL, phospho-Bad and Bcl-2), promoted activation of Bax and Bak and induced the release of cytochrome c into the cytoplasm. Treatment by Al2S4 let to the identification of early apoptotic events including Bcl-xL degradation, Bak activation and release of cytochrome c followed by late events including Bcl-2 proteolysis, Bax activation, Bad dephosphorylation, caspase activation, nuclear fragmentation and phosphatidylserine exposure.
Cerella
Claudia
C
Laboratoire de Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg, Rue Edward Steichen 9, 2540, Luxembourg, Luxembourg.
Scherer
Christiane
C
Cristofanon
Silvia
S
Henry
Estelle
E
Anwar
Awais
A
Busch
Corinna
C
Montenarh
Mathias
M
Dicato
Mario
M
Jacob
Claus
C
Diederich
Marc
M
D017209:Apoptosis / Q000187:drug effects*; D001782:Blood Donors; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006262:Health; D006801:Humans; D007938:Leukemia / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D020298:U937 Cells; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D013440:Sulfides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases