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

Abstract

Apoptosis is a process of active cell death characterized by cell surface blebbing, changes in membrane permeability, nuclear DNA condensation, and internucleosomal fragmentation.1) Several apoptotic pathways exist in cells responsive to apoptotic stimuli, and although each pathway is initiated by different mechanisms, they share a common final phase of apoptosis, which involves the activation of executioner caspases and the dismantling of substrates critical for cell survival.2) Classical apoptosis can be initiated via two distinct biochemical mechanisms, both of which result in caspase activation: (i) the extrinsic pathway that involves ligation of cell surface death receptors by their respective ligands, and (ii) the intrinsic mitochondrial pathway, which is largely controlled by the Bcl-2 family of pro-and anti-apoptotic proteins. It has been well established that the expressions of many gene products, such as Bid, Bax and Bcl-2, are critical for programmed cell death. Bcl-2 and Bcl-xl have anti-apoptotic functions, whereas Bid, Bax, Bim and Bcl-xs promote apoptosis. The balance between these two groups of genes determines the fate of cells in many systems, 3) and in particular, determines the depolarization of the mitochondrial membrane and the release of cytochrome c from mitochondria into the cytosol.4) This released cytochrome c then binds to apoptotic protease activating factor-1 (Apaf-1), which causes its oligomerization. 5) Procaspase-9 then binds to Apaf-1 oligomers to form a high-molecular-mass complex called apoptosome.6) In addition, this interaction activates caspase-9, which activates caspase-3 and thus triggers the irreversible apoptotic program. 7)Donepezil (R,S-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride) is prescribed for the treatment of cognitive dysfunction in Alzheimer's disease (AD).8) It prevents the hydrolysis of acetylcholine (ACh) and elevates ACh concentrations in the synaptic cleft, which increases cholinergic transmission.9) Previous studies haveshown that donepezil has neuroprotective effects in addition to its AChE-inhibiting action, and that these effects are due to the stimulation of nicotinic acetylcholine receptors, the activation of the phosphoinositide-3 kinase/Akt pathway, and the up-regulation of the anti-apoptotic protein Bcl-2. 10,11) However, no report has been issued on the molecular mechanism underlying the anti-proliferative effects of donepezil.In the present study, we demonstrate that donepezilinduced apoptosis involves the mitochondrial pathway via loss of mitochondrial membrane potential, a hallmark of permeability transition, and that this causes the release of cytochrome c to cytosol, and the sequential activations of caspases-8, -9, and -3 via the modulation of Bcl-2 in human promyelocytic leukemia HL-60 cells. Furthermore, this is the first report to show that donepezil induces apoptosis through a mitochondria-mediated caspase-dependent pathway. Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea: and d Eisai Korea ...

Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus

“…PGC-1α is the master regulator for mitochondrial biogenesis, and NRF-1 is a transcription regulator for nuclear-encoded mitochondrial genes [25]. Given that high concentrations of donepezil could induce apoptosis [26], we confirmed by Alamar Blue assay that mitochondrial biogenesis enhanced by donepezil was not a result of cell toxicity (data not shown). Taken together, these results show that donepezil induces mitochondrial biogenesis and promotes energy status by stimulating key transcription regulators.…”

Inhibition of acetylcholinesterase activity and β‑amyloid oligomer formation by 6‑bromotryptamine�A, a multi‑target anti‑Alzheimer's molecule

“…Notably, a number of AChE inhibitors are currently used or are under investigation for their potential application in cancer treatment. For instance, donepezil has been reported to induce apoptosis of HL-60 human promyelocytic leukemia cells (31). Galantamine has also been proven to produce anti-proliferation effects against 3T3 cells (28).…”

Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms

“…The cancer-sensitizing ability of DON and SID, which are aging-related repositioned drugs for Alzheimer's or erectile dysfunction, have been demonstrated in various cancer models (25)(26)(27)(28)(29), suggesting that they have potential as chemotherapeutic agents. In this study, DON and SID were found to sensitize P-gp-overexpressing anti-mitotic drug-resistant cancer cells.…”