title: Induction of apoptosis by carbazole alkaloids isolated from Murraya koenigii.
abstract: In the current study, we isolated 10 carbazole alkaloids from the plant species Murraya koenigii (Rutaceae), and examined their effects on the growth of the human leukemia cell line HL-60. Three carbazole alkaloids, mahanine (6), pyrayafoline-D (7) and murrafoline-I (9), showed significant cytotoxicity against HL-60 cells. Fluorescence microscopy with Hoechst 33342 staining revealed that the percentage of apoptotic cells with fragmented nuclei and condensed chromatin was increased in a time-dependent manner after treatment with each alkaloid. Interestingly, each carbazole alkaloid induced the loss of mitochondrial membrane potential. In addition, both caspase-9 and caspase-3 were also time-dependently activated upon treatment with the alkaloids. Caspase-9 and caspase-3 inhibitors suppressed apoptosis induced by these alkaloids. The results suggest that these three alkaloids induced apoptosis in HL-60 cells through activation of the caspase-9/caspase-3 pathway, through mitochondrial dysfunction.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Ito
authors.forename: M
authors.initials: M
authors.lastname: Itoigawa
authors.forename: K
authors.initials: K
authors.lastname: Nakao
authors.forename: T
authors.initials: T
authors.lastname: Murata
authors.forename: M
authors.initials: M
authors.lastname: Tsuboi
authors.forename: N
authors.initials: N
authors.lastname: Kaneda
authors.forename: H
authors.initials: H
authors.lastname: Furukawa
mesh_terms: D017209:Apoptosis; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D032101:Murraya / Q000737:chemistry*; D009842:Oligopeptides / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry*; D013997:Time Factors; D018675:Toxicity Tests
chemical_list: D002227:Carbazoles; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases