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 activiti...
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| Veröffentlicht in: | Biological & Pharmaceutical Bulletin 2010/06/01, Vol.33(6), pp.1054-1059 |
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| container_title | Biological & Pharmaceutical Bulletin |
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| creator | Ki, Yo Sook Park, Eun Young Lee, Heon-Woo Oh, Myung Sook Cho, Young-Wuk Kwon, Yunhee KIM Moon, Ji Hee Lee, Kyung-Tae |
| description | 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 (ΔΨm), 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. |
| doi_str_mv | 10.1248/bpb.33.1054 |
| format | Article |
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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 (ΔΨm), 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.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.33.1054</identifier><identifier>PMID: 20522977</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Annexin A5 - metabolism ; apoptosis ; Apoptosis - drug effects ; caspase ; Caspases - metabolism ; Cholinesterase Inhibitors - pharmacology ; Cytochromes c - metabolism ; Cytosol ; DNA Fragmentation ; Donepezil ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - pharmacology ; HeLa Cells ; HL-60 cell ; HL-60 Cells ; Humans ; Indans - pharmacology ; Leukemia, Promyelocytic, Acute - metabolism ; Leukemia, Promyelocytic, Acute - pathology ; Membrane Potential, Mitochondrial - drug effects ; mitochondrial membrane potential ; Piperidines - pharmacology ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; U937 Cells</subject><ispartof>Biological and Pharmaceutical Bulletin, 2010/06/01, Vol.33(6), pp.1054-1059</ispartof><rights>2010 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-7ba74788894eb668cbae1f3831443a20930e316f2545d7c557439e8032ec48003</citedby><cites>FETCH-LOGICAL-c691t-7ba74788894eb668cbae1f3831443a20930e316f2545d7c557439e8032ec48003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,4010,27900,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20522977$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ki, Yo Sook</creatorcontrib><creatorcontrib>Park, Eun Young</creatorcontrib><creatorcontrib>Lee, Heon-Woo</creatorcontrib><creatorcontrib>Oh, Myung Sook</creatorcontrib><creatorcontrib>Cho, Young-Wuk</creatorcontrib><creatorcontrib>Kwon, Yunhee KIM</creatorcontrib><creatorcontrib>Moon, Ji Hee</creatorcontrib><creatorcontrib>Lee, Kyung-Tae</creatorcontrib><creatorcontrib>aCollege of Pharmacy</creatorcontrib><creatorcontrib>Kyung Hee University</creatorcontrib><creatorcontrib>dEisai Korea Inc</creatorcontrib><creatorcontrib>bCollege of Medical Science</creatorcontrib><creatorcontrib>cDepartment of Biology</creatorcontrib><title>Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells</title><title>Biological & Pharmaceutical Bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>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. 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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.</description><subject>Annexin A5 - metabolism</subject><subject>apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>caspase</subject><subject>Caspases - metabolism</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cytochromes c - metabolism</subject><subject>Cytosol</subject><subject>DNA Fragmentation</subject><subject>Donepezil</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HeLa Cells</subject><subject>HL-60 cell</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Indans - pharmacology</subject><subject>Leukemia, Promyelocytic, Acute - metabolism</subject><subject>Leukemia, Promyelocytic, Acute - pathology</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>mitochondrial membrane potential</subject><subject>Piperidines - pharmacology</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>U937 Cells</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUU1vEzEQtRCIpoETd2SJA4d2g7927b21SqGpFIke4Gx5nQlx2LUXe_cQrvxxvElTJC5jS_PmvTfzEHpHyYIyoT41fbPgfEFJKV6gGeVCFiWj5Us0IzVVRUVLdYEuU9oTQiRh_DW6YKRkrJZyhv7cBQ89_HbtNTb4MQzgB3xrYTi0dhda5yENEE0C_OB3rnFDiNf5uxktJLw0qc-t4i4z-M1xsg_9EJJL2Hm8Gjvj8WMM3QHaYA-Ds3gN40_onMGrdVERvIS2TW_Qq61pE7x9eufo-5fP35arYv31_mF5uy5sVdOhkI2RQiqlagFNVSnbGKBbrjgVghtGak6A02rLSlFupC1LKXgNinAGVihC-Bx9PPH2Mfwa82K6c8lmB8ZDGJOWnNN8F0oz8sN_yH0Yo8_mdBaruZQq1zm6OqFsDClF2Oo-us7Eg6ZET9HoHI3mXE_RZPT7J86x6WDzjD1nkQH3J0DuOmva4Kfz_1O2STYutCFPZP68DyeVznke6adSU1IpJiapmxPTPg3mBzxLmZgjaOFsqzqV4_i5ZXcmavD8L_5Dtfs</recordid><startdate>2010</startdate><enddate>2010</enddate><creator>Ki, Yo Sook</creator><creator>Park, Eun Young</creator><creator>Lee, Heon-Woo</creator><creator>Oh, Myung Sook</creator><creator>Cho, Young-Wuk</creator><creator>Kwon, Yunhee KIM</creator><creator>Moon, Ji Hee</creator><creator>Lee, Kyung-Tae</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>2010</creationdate><title>Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells</title><author>Ki, Yo Sook ; 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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 (ΔΨm), to increase the release of cytochrome c to the cytosol, and to alter the expressions of Bcl-2 family proteins. 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| subjects | Annexin A5 - metabolism apoptosis Apoptosis - drug effects caspase Caspases - metabolism Cholinesterase Inhibitors - pharmacology Cytochromes c - metabolism Cytosol DNA Fragmentation Donepezil Dose-Response Relationship, Drug Enzyme Inhibitors - pharmacology HeLa Cells HL-60 cell HL-60 Cells Humans Indans - pharmacology Leukemia, Promyelocytic, Acute - metabolism Leukemia, Promyelocytic, Acute - pathology Membrane Potential, Mitochondrial - drug effects mitochondrial membrane potential Piperidines - pharmacology Proto-Oncogene Proteins c-bcl-2 - metabolism U937 Cells |
| title | Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells |
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