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Chemical Science Vol - 3 Issue - 5

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Chemical Science Vol -1

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

Content Provider	Royal Society of Chemistry (RSC)
Author	Che, Chi-Ming Siu, Fung-Ming Lok, Chun-Nam Lin, Iris Wing-Shan Lam, Tin-Lun Low, Kam-Hung Leung, Thomas Yun-Chung Yan, Kun
Copyright Year	2012
Abstract	Dirhodium(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 (Rh2L4, where L = μ2-OOCMe RhA, μ2-OOCnPr RhB, μ2-OOCiBu RhIsoVal, μ2-OOCiPr RhIsoButyl, μ2-OOCC2H4COPh RhPCOPh or μ2-OOCC3H6COPh 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.
Starting Page	1785
Ending Page	1793
Page Count	9
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	3
Issue Number	6
Journal	Chemical Science
DOI	10.1039/c2sc00620k
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Ubiquitin Deubiquitinating enzyme Oxaliplatin Gene Proteolysis DNA Carboplatin UPS Cytotoxicity Comet assay Cisplatin Proteasome
Content Type	Text
Resource Type	Article
Subject	Chemistry

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