Document Detail


Mechanism of mahanine-induced apoptosis in human leukemia cells (HL-60).
MedLine Citation:
PMID:  14667927     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mahanine, a carbazole alkaloid occurs in the edible part of Micromelum minutum, Murraya koenigii and related species has been found to induce apoptosis in human myeloid cancer cell (HL-60). Concentration of 10 microM mahanine caused a complete inhibition of cell proliferation and the induction of apoptosis in a time dependent manner. Mahanine-induced cell death was characterized with the changes in nuclear morphology, DNA fragmentation, activation of caspase like activities, poly(ADP-ribose) polymerase cleavage, release of cytochrome c into cytosol and stimulation of reactive oxygen species generation. The cell death was completely prevented by a pancaspase inhibitor benzyloxycarbonyl-L-aspart-1-yl-[(2,6-dichlorobenzoyl)oxy]methane (Z-Asp-CH(2)-DCB). Mahanine activated various caspases such as caspase-3, -6, -8 and -9 (like) activities but not caspase-1 like activity. More than 70% cell survival was observed in the presence of a caspase-3 inhibitor. In addition, co-treatment of cyclosporin A markedly increased the survival of mahanine-treated HL-60 cells. Flow cytometric analysis revealed that mahanine decreased the mitochondrial membrane potential of intact cells, and disrupted cell cycle progression by increasing the number of cells in sub-diploid region, concomitantly with the decrease of cells in diploid phases, particularly at late hours of apoptosis. The overall results suggest that mahanine down regulates cell survival factors by activation of caspase-3 through mitochondrial dependent pathway, and disrupts cell cycle progression.
Authors:
Molay Kumar Roy; Vipaporn Na Thalang; Gassinee Trakoontivakorn; Kazuhiko Nakahara
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  67     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2003-12-11     Completed Date:  2004-01-29     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  41-51     Citation Subset:  IM    
Affiliation:
Japan International Research Center for Agricultural Sciences (JIRCAS), 1-1 Owashi, Tsukuba, 305-8686, Ibaraki, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis*
Aspartic Acid / analogs & derivatives*,  pharmacology
Carbazoles / pharmacology*
Caspase 3
Caspases / antagonists & inhibitors,  metabolism*
Cell Cycle / drug effects
Cell Division / drug effects
Cysteine Proteinase Inhibitors / pharmacology
Cytochromes c / metabolism
Cytosol / metabolism
DNA / drug effects,  metabolism
DNA Fragmentation / drug effects
HL-60 Cells
Humans
Leukemia / pathology
Mitochondria / drug effects,  metabolism
Oligopeptides / pharmacology
Poly(ADP-ribose) Polymerases
Protease Inhibitors / pharmacology
Proteins / metabolism
Reactive Oxygen Species / metabolism*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Carbazoles; 0/Cysteine Proteinase Inhibitors; 0/Oligopeptides; 0/Protease Inhibitors; 0/Proteins; 0/Reactive Oxygen Species; 0/acetyl-aspartyl-glutamyl-valyl-aspartal; 0/acetyl-leucyl-glutamyl-histidyl-aspartal; 0/benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene; 0/mahanine; 56-84-8/Aspartic Acid; 9007-43-6/Cytochromes c; 9007-49-2/DNA; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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