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Article: Anticancer dirhodium(ii,ii) carboxylates as potent inhibitors of ubiquitin-proteasome system

TitleAnticancer dirhodium(ii,ii) carboxylates as potent inhibitors of ubiquitin-proteasome system
Authors
Issue Date2012
PublisherRoyal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/publishing/journals/sc/About.asp
Citation
Chemical Science, 2012, v. 3 n. 6, p. 1785-1793 How to Cite?
AbstractDirhodium(ii,ii) carboxylates are documented to exhibit both in vitro and in vivo anticancer properties. In literatures, DNA is a proposed molecular target of anticancer active dirhodium(ii,ii) compounds. Herein, we provide compelling evidences that for the dirhodium(ii,ii) carboxylates examined in this work (Rh 2L 4, where L = μ 2-OOCMe RhA, μ 2-OOCnPr RhB, μ 2-OOCiBu RhIsoVal, μ 2-OOCiPr RhIsoButyl, μ 2-OOCC 2H 4COPh RhPCOPh or μ 2-OOCC 3H 6COPh RhBCOPh), a prominent mechanism of action is the inhibition of ubiquitin-proteasome system (UPS). Using an unbiased connectivity map analysis, the changes in global gene expression upon treatment of cells with dirhodium(ii,ii) acetate and butyrate are similar to that of proteasome inhibitors. Cellular studies revealed that dirhodium(ii,ii) butyrate at submicromolar concentrations exerts a strong inhibition of UPS, attributable to impairment of proteasomal proteolysis and deubiquitinating enzyme activities. The UPS inhibitory potencies of the dirhodium(ii,ii) carboxylates also exhibit strong correlation with the cytotoxicities. Of note, the dirhodium(ii,ii) carboxylates inhibit UPS at concentrations that were at least 10-fold lower than that required for eliciting DNA damage as determined by comet assay. While cisplatin, oxaliplatin and carboplatin readily induce significant double strand break as indicated by γ-H2AX induction, the dirhodium(ii,ii) carboxylates do not. Our findings revealed that the dirhodium(ii,ii) carboxylates exhibit potent UPS inhibitory property which is linked to their cytotoxic actions. © 2012 The Royal Society of Chemistry.
Persistent Identifierhttp://hdl.handle.net/10722/146808
ISSN
2015 Impact Factor: 9.144
2015 SCImago Journal Rankings: 4.974
ISI Accession Number ID
Funding AgencyGrant Number
Areas of Excellence SchemeAoE/P-10-01
ITF-Tier 2ITS/134/09FP
Funding Information:

This work was supported by the Areas of Excellence Scheme (AoE/P-10-01) adminstrated by the University Grants Committee of Hong Kong SAR, China and the ITF-Tier 2 project (ITS/134/09FP) administrated by the Innovation and Technology Commision of Hong Kong SAR, China. FMS deeply acknowledges the help from the Developmental Therapeutics Program (National Cancer Institute, National Institutes of Health, Bethesda, USA) to perform the NCI-60 cytotoxicity profiling study for RhA and RhB.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorSiu, FMen_HK
dc.contributor.authorLin, IWSen_HK
dc.contributor.authorYan, Ken_HK
dc.contributor.authorLok, CNen_HK
dc.contributor.authorLow, KHen_HK
dc.contributor.authorLeung, TYCen_HK
dc.contributor.authorLam, TLen_HK
dc.contributor.authorChe, CMen_HK
dc.date.accessioned2012-05-22T01:37:20Z-
dc.date.available2012-05-22T01:37:20Z-
dc.date.issued2012en_HK
dc.identifier.citationChemical Science, 2012, v. 3 n. 6, p. 1785-1793en_HK
dc.identifier.issn2041-6520en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146808-
dc.description.abstractDirhodium(ii,ii) carboxylates are documented to exhibit both in vitro and in vivo anticancer properties. In literatures, DNA is a proposed molecular target of anticancer active dirhodium(ii,ii) compounds. Herein, we provide compelling evidences that for the dirhodium(ii,ii) carboxylates examined in this work (Rh 2L 4, where L = μ 2-OOCMe RhA, μ 2-OOCnPr RhB, μ 2-OOCiBu RhIsoVal, μ 2-OOCiPr RhIsoButyl, μ 2-OOCC 2H 4COPh RhPCOPh or μ 2-OOCC 3H 6COPh RhBCOPh), a prominent mechanism of action is the inhibition of ubiquitin-proteasome system (UPS). Using an unbiased connectivity map analysis, the changes in global gene expression upon treatment of cells with dirhodium(ii,ii) acetate and butyrate are similar to that of proteasome inhibitors. Cellular studies revealed that dirhodium(ii,ii) butyrate at submicromolar concentrations exerts a strong inhibition of UPS, attributable to impairment of proteasomal proteolysis and deubiquitinating enzyme activities. The UPS inhibitory potencies of the dirhodium(ii,ii) carboxylates also exhibit strong correlation with the cytotoxicities. Of note, the dirhodium(ii,ii) carboxylates inhibit UPS at concentrations that were at least 10-fold lower than that required for eliciting DNA damage as determined by comet assay. While cisplatin, oxaliplatin and carboplatin readily induce significant double strand break as indicated by γ-H2AX induction, the dirhodium(ii,ii) carboxylates do not. Our findings revealed that the dirhodium(ii,ii) carboxylates exhibit potent UPS inhibitory property which is linked to their cytotoxic actions. © 2012 The Royal Society of Chemistry.en_HK
dc.languageeng-
dc.publisherRoyal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/publishing/journals/sc/About.aspen_HK
dc.relation.ispartofChemical Scienceen_HK
dc.titleAnticancer dirhodium(ii,ii) carboxylates as potent inhibitors of ubiquitin-proteasome systemen_HK
dc.typeArticleen_HK
dc.identifier.emailLok, CN:cnlok@hku.hken_HK
dc.identifier.emailChe, CM:cmche@hku.hken_HK
dc.identifier.authorityLok, CN=rp00752en_HK
dc.identifier.authorityChe, CM=rp00670en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1039/c2sc00620ken_HK
dc.identifier.scopuseid_2-s2.0-84864200255en_HK
dc.identifier.hkuros199547-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84864200255&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume3en_HK
dc.identifier.issue6en_HK
dc.identifier.spage1785en_HK
dc.identifier.epage1793en_HK
dc.identifier.eissn2041-6539-
dc.identifier.isiWOS:000304365000006-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectDiscovery and Pre-Clinical Evaluation of Promising Metal-Based Anti-Cancer Drug Leads-
dc.identifier.scopusauthoridSiu, FM=55195027400en_HK
dc.identifier.scopusauthoridLin, IWS=55320482100en_HK
dc.identifier.scopusauthoridYan, K=35340293700en_HK
dc.identifier.scopusauthoridLok, CN=7006410829en_HK
dc.identifier.scopusauthoridLow, KH=7102180516en_HK
dc.identifier.scopusauthoridLeung, TYC=40861329100en_HK
dc.identifier.scopusauthoridLam, TL=55319843900en_HK
dc.identifier.scopusauthoridChe, CM=7102442791en_HK

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