A Ruthenium Antimetastasis Agent Forms Specific Histone Protein Adducts in the Nucleosome Core

Wu, Bin; Ong, Michelle S.; Groessl, Michael; Adhireksan, Zenita; Hartinger, Christian G.; Dyson, Paul J.; Davey, C.A.

doi:10.1002/chem.201100298

Cited by 170 publications

(172 citation statements)

References 42 publications

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“…However, in nucleus, the chromatin (histone proteins and DNA) are also potential therapeutic target of many drugs. One of the ruthenium containing drugs RAPTA-C has been shown to interact with nucleosome core particle (NCP) by making adducts with histone proteins [23]. A similar kind of histone adduct has been observed with acrolein [42].…”

Section: Discussionmentioning

confidence: 91%

“…One of the ruthenium containing drug RAPTA-C has been shown to interact with nucleosome core particle (NCP) by making histone protein adducts [23]. We therefore made soluble chromatin as described in Section 2 and gel filtration chromatography was performed to isolate the mononucleosomal fraction.…”

Section: Kp1019 Evicts Histones From Soluble Chromatin and Interacts mentioning

confidence: 99%

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Anti‐cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae

et al. 2014

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a b s t r a c t KP1019 comprises a class of ruthenium compounds having promising anticancer activity. Here, we investigated the molecular targets of KP1019 using Saccharomyces cerevisiae as a model organism. Our results revealed that in the absence of the N-terminal tail of histone H3, the growth inhibitory effect of KP1019 was markedly enhanced. Furthermore, H3K56A or rtt109D mutants exhibit hypersensitivity for KP1019. Moreover, KP1019 evicts histones from the mononucleosome and interacts specifically with histone H3. We have also shown that KP1019 treatment causes induction of Ribonucleotide Reductase (RNR) genes and degradation of Sml1p. Our results also suggest that DNA damage induced by KP1019 is primarily repaired through double-strand break repair (DSBR). In summary, KP1019 targets histone proteins, with important consequences for DNA damage responses and epigenetics.

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Section: Discussionmentioning

confidence: 91%

Section: Kp1019 Evicts Histones From Soluble Chromatin and Interacts mentioning

confidence: 99%

Anti‐cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae

et al. 2014

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“…widely studied, and several others also show promise. [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] Recently, different groups have investigated the chemical and biological activity of analogous half-sandwich arene osmium complexes. [77][78][79][80][81][82][83][84][85] Osmium, the heavier congener of ruthenium and a third row transition metal, commonly exhibits slower kinetics than ruthenium, and is often considered to be relatively inert.…”

Section: Platinum Complexesmentioning

confidence: 99%

100 years of metal coordination chemistry: from Alfred Werner to anticancer metallodrugs

Barry

Sadler

2014

Pure and Applied Chemistry

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“…30 In fact, recent studies have revealed that DNA is not always the primary target for some ruthenium anticancer compounds and that they actually bind more strongly to proteins or enzymes than to DNA. 4,31 Hence, it seems important not only to develop efficient targeting strategies to deliver metallodrugs selectively into cancer cells, but also to direct them towards a particular biological target.…”

Section: Introductionmentioning

confidence: 99%

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

et al. 2013

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&These two authors contributed equally to this work. ABSTRACTA straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino-and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η 6 -p-cym)RuCl(PPh 3 ) 2 ] + , allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N'-di-Boc-N"-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semi-preparative HPLC and characterized by ESI and MALDI-TOF MS and NMR spectroscopy. The cytotoxicity of the compounds was tested in and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, neomycin-ruthenium conjugate (2) displayed moderate anti-proliferative activity in both cancer cell lines (IC 50 ≈ 80 µM), whereas that of the neamine conjugate (4) was inactive (IC 50 ≈ 200 µM).However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC 50 = 7.17 µM in DU-145 and IC 50 = 11.33 µM in MCF-7). Although the same ranking in anti-proliferative activity was found in the non-tumorigenic cell line (3 >> 2 > 4), IC 50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g. IC 50 = 49.4 µM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC 50 = 12.75 µM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher anti-proliferative activity of 3.Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular 3 accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

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A Ruthenium Antimetastasis Agent Forms Specific Histone Protein Adducts in the Nucleosome Core

Cited by 170 publications

References 42 publications

Anti‐cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae

Anti‐cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae

100 years of metal coordination chemistry: from Alfred Werner to anticancer metallodrugs

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

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