title: Allicin inhibits cell growth and induces apoptosis through the mitochondrial pathway in HL60 and U937 cells.
abstract: In this article, the effects of allicin, a biological active compound of garlic, on HL60 and U937 cell lines were examined. Allicin induced growth inhibition and elicited apoptotic events such as blebbing, mitochondrial membrane depolarization, cytochrome c release into the cytosol, activation of caspase 9 and caspase 3 and DNA fragmentation. Pretreatment of HL60 cells with cyclosporine A, an inhibitor of the mitochondrial permeability transition pore (mPTP), inhibited allicin-treated cell death. HL60 cell survival after 1 h pretreatment with cyclosporine A, followed by 16 h in presence of allicin (5 microM) was approximately 80% compared to allicin treatment alone (approximately 50%). Also N-acetyl cysteine, a reduced glutathione (GSH) precursor, prevented cell death. The effects of cyclosporine A and N-acetyl cysteine suggest the involvement of mPTP and intracellular GSH level in the cytotoxicity. Indeed, allicin depleted GSH in the cytosol and mitochondria, and buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly augmented allicin-induced apoptosis. In HL60 cells treated with allicin (5 microM, 30 min) the redox state for 2GSH/oxidized glutathione shifted from EGSH -240 to -170 mV. The same shift was observed in U937 cells treated with allicin at a higher concentration for a longer period of incubation (20 microM, 2 h). The apoptotic events induced by various concentrations of allicin correlate to intracellular GSH levels in the two cell types tested (HL60: 3.7 nmol/10(6) cells; U937: 7.7 nmol/10(6) cells). The emerging mechanistic basis for the antiproliferative function of allicin, therefore, involves the activation of the mitochondrial apoptotic pathway by GSH depletion and by changes in the intracellular redox status.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Miron
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Meir
authors.initials: M
authors.lastname: Wilchek
authors.affiliation: Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Sharp
authors.affiliation: Gifu International Institute of Biotechnology, Kakamigahara, Gifu 504-0838, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Gifu International Institute of Biotechnology, Kakamigahara, Gifu 504-0838, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Naoi
authors.affiliation: Gifu International Institute of Biotechnology, Kakamigahara, Gifu 504-0838, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nozawa
authors.affiliation: Gifu International Institute of Biotechnology, Kakamigahara, Gifu 504-0838, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004220:Disulfides; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000032:analysis; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010084:Oxidation-Reduction; D013441:Sulfinic Acids / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004220:Disulfides; D004791:Enzyme Inhibitors; D013441:Sulfinic Acids; C006452:allicin; D019328:Buthionine Sulfoximine; D045304:Cytochromes c; D020169:Caspases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione