A novel mechanism of irinotecan targeting MDM2 and Bcl-xL

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dc.contributor.authorLee, Boahko
dc.contributor.authorMin, Jeong A.ko
dc.contributor.authorNashed, Abdullateefko
dc.contributor.authorLee, Sang-Okko
dc.contributor.authorYoo, Jae Chealko
dc.contributor.authorChi, Seung-Wookko
dc.contributor.authorYi, Gwan-Suko
dc.date.accessioned2019-07-05T05:50:04Z-
dc.date.available2019-07-05T05:50:04Z-
dc.date.created2019-07-01-
dc.date.issued2019-06-
dc.identifier.citationBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.514, no.2, pp.518 - 523-
dc.identifier.issn0006-291X-
dc.identifier.urihttp://hdl.handle.net/10203/262987-
dc.description.abstractIrinotecan is a strong anticancer drug whose mechanismof action has been reported only for the inhibition of DNA topoisomerase I (Topo I) through its active metabolite SN-38. In this study, we present a new mechanism of Irinotecan which inhibits the activities of MDM2, an E3 ligase of tumour suppressor p53, and Bcl-xL, an anti-apoptotic protein, through direct binding. In our structure modelling study, Irinotecan could fit to the binding sites of MDM2 and Bcl-xL for their known drugs, Nutlin-3 and ABT-737, with a better binding affinity than to Topo I. The direct binding of Irinotecan to both proteins was confirmed through a NMR study. We further showed that Irinotecan increased the amount of p53 only in the presence of MDM2 and inhibited the physical interaction of Bcl-xL with Bim, a core pro-apoptotic protein. In addition, we demonstrated that Irinotecan induced the down regulation of proliferation and strong G2/M arrest in HCT116 colon cancer cells shortly after treatment. Collectively, we suggest a new mechanism of action for Irinotecan as a dual target inhibitor of MDM2 and Bcl-xL facilitating the anticancer activities mediated by p53 and Bcl-xL interaction partners. (C) 2019 Elsevier Inc. All rights reserved.-
dc.languageEnglish-
dc.publisherACADEMIC PRESS INC ELSEVIER SCIENCE-
dc.titleA novel mechanism of irinotecan targeting MDM2 and Bcl-xL-
dc.typeArticle-
dc.identifier.wosid000470803700025-
dc.identifier.scopusid2-s2.0-85066111430-
dc.type.rimsART-
dc.citation.volume514-
dc.citation.issue2-
dc.citation.beginningpage518-
dc.citation.endingpage523-
dc.citation.publicationnameBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS-
dc.identifier.doi10.1016/j.bbrc.2019.04.009-
dc.contributor.localauthorYi, Gwan-Su-
dc.contributor.nonIdAuthorMin, Jeong A.-
dc.contributor.nonIdAuthorLee, Sang-Ok-
dc.contributor.nonIdAuthorChi, Seung-Wook-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorIrinotecan-
dc.subject.keywordAuthorDual-targets-
dc.subject.keywordAuthorMDM2-
dc.subject.keywordAuthorBcl-xL-
dc.subject.keywordAuthorStructure modelling-
dc.subject.keywordAuthorNMR-
dc.subject.keywordPlusTOPOISOMERASE-I-
dc.subject.keywordPlusP53-
dc.subject.keywordPlusANTAGONISTS-
dc.subject.keywordPlusINHIBITORS-
dc.subject.keywordPlusABT-737-
dc.subject.keywordPlusLIGASE-
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