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dc.contributor.author최정혜-
dc.date.accessioned2018-03-23T06:40:08Z-
dc.date.available2018-03-23T06:40:08Z-
dc.date.issued2012-12-
dc.identifier.citationInvestigational New Drugs, 2012, 30(6), P.2284-2293en_US
dc.identifier.issn0167-6997-
dc.identifier.issn1573-0646-
dc.identifier.urihttp://link.springer.com/article/10.1007/s10637-012-9814-x-
dc.identifier.urihttp://hdl.handle.net/20.500.11754/51411-
dc.description.abstractSubstituted 2-pyrones are important structural sub-units present in a number of natural products having broad range of biological activity. However, little is known about the anti-cancer effect of 2-pyrone derivatives including leukemia. Therefore, this present study was undertaken to investigate the effect of 2-pyrone derivatives in human acute myeloid leukemia (AML). Among 23 synthesized derivatives, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (code name; pyrone 9) showed the most potent antileukemic activity with 5? 10(-6) M to 5??10(-5) M of IC(50) in various AML cell lines as well as primary leukemic blasts from AML patients, while normal peripheral blood mononuclear cells was not affected by pyrone 9. Flow cytometric analysis indicated that pyrone 9 induced the G1 and G2 phase dual arrest of the cell cycle in HL-60 cells. To address the mechanism of the antileukemic effect of pyrone 9, we examined the effect of pyrone 9 on cell cycle-related proteins in HL-60 cell. The levels of CDK2, CDK4, CDK6, CDK1, cyclin B1 and cyclin E were decreased; in contrast, cyclin A was not altered. In addition, pyrone 9 not only increased the p27 level but also enhanced its binding to with CDK2, CDK4 and CDK6 which resulted in the reduction of CDK2-, CDK4- and CDK6-associated kinase activities. Pyrone 9 also induced the apoptosis in HL-60 cells. The apoptotic process of HL-60 cells was associated with increased Bax, decreased Bcl-2 and activation of caspase-8, -9, -3 and PARP. Antileukemic effect of pyrone 9 was associated with activation of mitogen-activated protein kinase (MAPK) pathway, as evidenced by activation of p-ERK and p38 MAPK. In addition, pyrone 9 was influenced PI3 kinase pathway. Expressions of p-Akt (ser473), p-Raf, and p-PDK were down-regulated; in contrast, those of PTEN and p-PTEN were up-regulated. Furthermore, pyrone 9 suppressed NF-κB pathway signaling. To gain insights into the antileukemic activity of pyrone 9 in vivo, BALB/c mouse leukemic model was established using intraperitoneal inoculation of syngeneic WEHI-3BD(+) mouse leukemic cells. Pyrone 9 inhibited in vitro and in vivo the growth of WEHI-3BD(+) cells, and ultimately, prolonged the survival of pyrone 9-treated mice. These findings suggest that the pyrone 9 inhibits the cell proliferation of human AML cell line, HL-60, through MAPK and PI3 kinase pathway as well as induction of cell cycle arrest. In particular, pyrone 9 prolonged the survival of pyrone 9-treated leukemic mice.en_US
dc.description.sponsorshipThis work was supported by a grant from the Ministry of Knowledge Economy, Republic of Koreaen_US
dc.language.isoenen_US
dc.publisherSpringer Science + Business Mediaen_US
dc.subjectAMLen_US
dc.subject2-pyrone derivativesen_US
dc.subjectAnti-leukemicen_US
dc.subjecteffecten_US
dc.subjectMAPKen_US
dc.subjectPI3 kinaseen_US
dc.titleAnti-leukemic effect of 2-pyrone derivatives via MAPK and PI3 kinase pathwaysen_US
dc.typeArticleen_US
dc.relation.no6-
dc.relation.volume30-
dc.identifier.doi10.1007/s10637-012-9814-x-
dc.relation.page2284-2293-
dc.relation.journalINVESTIGATIONAL NEW DRUGS-
dc.contributor.googleauthorYoon, Jin Sun-
dc.contributor.googleauthorWon, Young Woong-
dc.contributor.googleauthorKim, Seo Ju-
dc.contributor.googleauthorOh, Suk Joong-
dc.contributor.googleauthorKim, Eun Shil-
dc.contributor.googleauthorKim, Byoung Kook-
dc.contributor.googleauthorCho, Cheon Gyu-
dc.contributor.googleauthorChoi, Jung Hye-
dc.contributor.googleauthorPark, Byeong Bae-
dc.contributor.googleauthorLee, Min Ho-
dc.relation.code2012204426-
dc.sector.campusS-
dc.sector.daehakCOLLEGE OF MEDICINE[S]-
dc.sector.departmentDEPARTMENT OF MEDICINE-
dc.identifier.pidjhcmd-
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COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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