Donepezil, a potent acetylcholinesterase inhibitor, induces caspase-dependent apoptosis in human promyelocytic leukemia HL-60 cells.
Although donepezil, a potent acetylcholinesterase (AChE) inhibitor, has been used to treat Alzheimer's disease (AD) due to its neuroprotective effects, its mode of action to inhibit the growth of cancer cells is poorly understood. In the present study, we investigated the pro-apoptotic activities of donepezil in HL-60 human promyelocytic leukemia cells and the underlying molecular mechanism involved. It was found that donepezil induced the apoptosis of HL-60 and U937 cells in a dose- and time-dependent manner, as evidenced by the formation of DNA fragmentation and the accumulation of positive cells for Annexin V. In addition, the activations of caspase-8, -9, and -3 were significantly increased 36 h after donepezil treatment. Furthermore, the broad caspase inhibitor (z-VAD-fmk) blocked donepezil-induced apoptosis. In addition, donepezil was found to cause the loss of mitochondrial membrane potential (DeltaPsi(m)), to increase the release of cytochrome c to the cytosol, and to alter the expressions of Bcl-2 family proteins. Taken together, these results demonstrate for the first time that donepezil displayed an induction of apoptosis in HL-60 cells via a mitochondria-mediated caspase-dependent pathway.
College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Yo Sook
YS
Ki
Eun Young
EY
Park
Heon-Woo
HW
Lee
Myung Sook
MS
Oh
Young-Wuk
YW
Cho
Yunhee Kim
YK
Kwon
Ji Hee
JH
Moon
Kyung-Tae
KT
Lee
D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol; D053938:DNA Fragmentation; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020298:U937 Cells
D017304:Annexin A5; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D007189:Indans; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D000077265:Donepezil; D045304:Cytochromes c; D020169:Caspases