Mahanine, a carbazole alkaloid from Micromelum minutum, inhibits cell growth and induces apoptosis in U937 cells through a mitochondrial dependent pathway.
1 Mahanine, a naturally occurring carbazole alkaloid in some Asian vegetables, has been shown to exhibit antimutagenicity, antimicrobial activity, cytotoxicity, and other biological properties. 2 In the present study, we investigated the effect of mahanine on the activation of the apoptotic pathway in human leukemia U937 cells. Various end points were used to screen for apoptosis: Morphological changes in cells, the relative numbers of viable and apoptotic cells; translocation of membrane bound phosphatidylserine and DNA analysis. 3 We found that mahanine-induced apoptosis in U937 cells involved activation of caspases, including caspase-3, release of cytochrome c into cytosol, loss of mitochondrial membrane permeability, and decreased levels of cellular ATP. 4 Pretreatment of cells with cyclosporine A, prior to/concomitant with exposure to mahanine, effectively prevented the deleterious effects of the alkaloid on cellular integrity and viability. 5 As mitochondrial permeability is known to be important in the regulation of cytochrome c release, our observations indicate that mitochondria are the principal target of mahanine. More specifically, we propose that mahanine causes the mitochondrial membranes to lose their permeability, resulting in caspase-3 activation and apoptosis.
Roy
Molay Kumar
MK
Japan International Research Center for Agricultural Sciences, Tsukuba, Ibaraki 305-8686, Japan. mkroy@affrc.go.jp
Thalang
Vipaporn Na
VN
Trakoontivakorn
Gassinee
G
Nakahara
Kazuhiko
K
D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002227:Carbazoles / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009707:Nucleosomes / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport; D027821:Rutaceae; D020298:U937 Cells
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D002227:Carbazoles; D007166:Immunosuppressive Agents; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009707:Nucleosomes; C465290:mahanine; D016572:Cyclosporine; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases