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dc.contributor.authorWang, Huabo
dc.contributor.authorTeriete, Peter
dc.contributor.authorHu, Angela
dc.contributor.authorRaveendra-Panickar, Dhanya
dc.contributor.authorPendelton, Kelsey
dc.contributor.authorLazo, John S
dc.contributor.authorEiseman, Julie
dc.contributor.authorHolien, Toril
dc.contributor.authorMisund, Kristine
dc.contributor.authorOliynyk, Ganna
dc.contributor.authorArsenian-Henriksson, Marie
dc.contributor.authorCosford, Nicholas DP
dc.contributor.authorSundan, Anders
dc.contributor.authorProchownik, Edward V
dc.date.accessioned2017-12-02T10:55:26Z
dc.date.available2017-12-02T10:55:26Z
dc.date.created2016-01-07T19:31:50Z
dc.date.issued2015
dc.identifier.citationOncoTarget. 2015, 6 (32), 32380-32395.nb_NO
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/11250/2468832
dc.description.abstractMany oncogenic signals originate from abnormal protein-protein interactions that are potential targets for small molecule inhibitors. However, the therapeutic disruption of these interactions has proved elusive. We report here that the naturally-occurring triterpenoid celastrol is an inhibitor of the c-Myc (Myc) oncoprotein, which is over-expressed in many human cancers. Most Myc inhibitors prevent the association between Myc and its obligate heterodimerization partner Max via their respective bHLH-ZIP domains. In contrast, we show that celastrol binds to and alters the quaternary structure of the pre-formed dimer and abrogates its DNA binding. Celastrol contains a reactive quinone methide group that promiscuously forms Michael adducts with numerous target proteins and other free sulfhydryl-containing molecules. Interestingly, triterpenoid derivatives lacking the quinone methide showed enhanced specificity and potency against Myc. As with other Myc inhibitors, these analogs rapidly reduced the abundance of Myc protein and provoked a global energy crisis marked by ATP depletion, neutral lipid accumulation, AMP-activated protein kinase activation, cell cycle arrest and apoptosis. They also inhibited the proliferation of numerous established human cancer cell lines as well as primary myeloma explants that were otherwise resistant to JQ1, a potent indirect Myc inhibitor. N-Myc amplified neuroblastoma cells showed similar responses and, in additional, underwent neuronal differentiation. These studies indicate that certain pharmacologically undesirable properties of celastrol such as Michael adduct formation can be eliminated while increasing selectivity and potency toward Myc and N-Myc. This, together with their low in vivo toxicity, provides a strong rationale for pursuing the development of additional Myc-specific triterpenoid derivatives.nb_NO
dc.language.isoengnb_NO
dc.publisherImpact Journalnb_NO
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleDirect inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoidsnb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.description.versionpublishedVersionnb_NO
dc.source.pagenumber32380-32395nb_NO
dc.source.volume6nb_NO
dc.source.journalOncoTargetnb_NO
dc.source.issue32nb_NO
dc.identifier.doi10.18632/oncotarget.6116
dc.identifier.cristin1308179
dc.relation.projectStiftelsen Kristian Gerhard Jebsen: SKGJ-MED-007nb_NO
dc.relation.projectNorges forskningsråd: 223255nb_NO
dc.relation.projectKreftforeningen: 2215992nb_NO
dc.description.localcode© 2015 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.nb_NO
cristin.unitcode194,65,15,0
cristin.unitnameInstitutt for klinisk og molekylær medisin
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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