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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.

Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells