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Victor E. Marquez - One of the best experts on this subject based on the ideXlab platform.
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MoleculAr Medicine Epigenetic RegulAtion of EndotheliAl LineAge Committed Genes in Pro-Angiogenic HemAtopoietic And EndotheliAl Progenitor
2016Co-Authors: Kisho Ohtani, Victor E. Marquez, Georgios J. Vlachojannis, Masamichi Koyanagi, Jes Niels Boeckel, Carmen Urbich, Halvard Bonig, Andreas M. Zeiher, Ra Farcas, Stefanie DimmelerAbstract:RAtionAle: ProAngiogenic hemAtopoietic And endotheliAl progenitor cells (EPCs) contribute to postnAtAl neovAs-culArizAtion, but the mechAnisms regulAting differentiAtion to the endotheliAl lineAge Are uncleAr. Objective: To elucidAte the epigenetic control of endotheliAl gene expression in proAngiogenic cells And EPCs. Methods And Results: Here we demonstrAte thAt the endotheliAl nitric oxide synthAse (eNOS) promoter is epigeneticAlly silenced in proAngiogenic cells (eArly EPCs), CD34 cells, And mesoAngioblAsts by DNA methylAtion And prominent repressive histone H3K27me3 mArks. In order to reverse epigenetic silencing to fAcilitAte endotheliAl commitment, we used 3-DeAzAneplAnocin A, which inhibits the histone methyltrAnsferAse enhAncer of zest homolog 2 And, thereby, reduces H3K27me3. 3-DeAzAneplAnocin A wAs not sufficient to increAse eNOS expression, but the combinAtion of 3-DeAzAneplAnocin A And the histone deAcetylAse inhibitor TrichostAtin A Augmented eNOS expression, indicAting thAt the concomitAnt inhibition of silencing histone modificAtion And enhAncement of ActivAting histone modificAtion fAcilitAtes eNOS expression. In ischemic tissue, hypoxiA plAys A role in recruiting progenitor cells. Therefore, we exAmined the effect of hypoxiA on epigenetic modificAtions. HypoxiA modulAted the bAlAnce of repressive to Active histone mArks And increAsed eNOS mRNA expression. The reduction of repressive H3K27me3 wAs AssociAted with An increAse of the histone demethylAse Jmjd3. Silencing of Jmjd3 induced Apoptosis And senescence in proAngiogenic cells And inhibited hypoxiA-mediAted up-regulAtio
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PreclinicAl Development MoleculAr MechAnisms Involved in the Synergistic InterAction of the EZH2 Inhibitor 3-DeAzAneplAnocin A with GemcitAbine in PAncreAtic CAncer Cells
2016Co-Authors: Amir Avan, Victor E. Marquez, Francesco Crea, Elisa Paolicchi, Niccola Funel, Elena Galvani, Richard J. Honeywell, Romano Danesi, Godefridus J. Peters, Elisa GiovannettiAbstract:PAncreAtic ductAl AdenocArcinomA (PDAC) is chArActerized by overexpression of enhAncer of Zeste homolog-2 (EZH2), which plAys A pivotAl role in cAncer stem cell (CSC) self-renewAl through methylAtion of histone H3 lysine-27 (H3K27me3). AgAinst this bAckground, EZH2 wAs identified As An AttrActive tArget, And we investigAted the interAction of the EZH2 inhibitor DZNeP with gemcitAbine. EZH2 expression wAs detected by quAntitAtive PCR in 15 PDAC cells, including seven primAry cell cultures, showing thAt expression vAlues correlAted with their originAtor tumors (SpeArmAn R2 0.89, P 0.01). EZH2 expression in cAncer cells wAs significAntly higher thAn in normAl ductAl pAncreAtic cells And fibroblAsts. The 3-DeAzAneplAnocin A (DZNeP; 5 mmol/L, 72-hour exposure) modulAted EZH2 And H3K27me3 protein expression And synergisticAlly enhAnced the AntiproliferAtive Activity of gemcitAbine, with combinAtion index vAlues of 0.2 (PANC-1), 0.3 (MIA-PACA-2), And 0.7 (LPC006). The drug combinAtion reduced the percentAges of cells in G2–M phAse (e.g., from 27 % to 19 % in PANC-1, P < 0.05) And significAntly increAsed Apoptosis compAred with gemcitAbine Alone. Moreover, DZNeP enhAnced the mRNA And protein expression of the nucleoside trAnsporters hENT1/hCNT1, possibly becAuse of the significAnt reduction of deoxynucleotide content (e.g., 25 % reduction of deoxycytidine nucleotides in PANC-1), As detected by liquid chromAtogrAphy/tAndem mAss spectrometry. DZNeP decreAsed cell migrAtion, which wAs Addi-tionAlly reduced by DZNeP/gemcitAbine combinAtion (–20 % in LPC006, After 8-hour exposure, P < 0.05) And AssociAted with increAsed E-cAdherin mRNA And protein expression. Furthermore, DZNeP And DZNeP/gemcitAbine combinAtion significAntly reduced the volume of PDAC spheroids growing in CSC-selective medium And decreAsed the proportion of CD133þ cells. All these moleculAr mechAnisms underlying the synergism of DZNeP/gemcitAbine combinAtion support further studies on this novel therApeutic ApproAch for treAtment of PDACs. Mol CAncer Ther; 11(8); 1735–46. 2012 AACR
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DZNep Is A GlobAl Histone MethylAtion Inhibitor thAt ReActivAtes DevelopmentAl Genes Not Silenced by DNA MethylAtion
2015Co-Authors: Tina Branscombe Mir, Victor E. Marquez, Connie C. Cortez, Christine B. Yoo, Gangning Liang, Masanobu Abe, Theresa K. Kelly, Peter A. JonesAbstract:DNA methylAtion, histone modificAtions, And nucleosomAl occupAncy collAborAte to cAuse silencing of tumor-relAted genes in cAncer. The development of drugs thAt tArget these processes is therefore importAnt for cAncer therApy. Inhibitors of DNA methylAtion And histone deAcetylAtion hAve been Approved by the Food And Drug AdministrAtion for treAtment of hemAtologic mAlignAncies. However, drugs thAt tArget other mechAnisms still need to be developed. Recently, 3-DeAzAneplAnocin A (DZNep) wAs reported to selectively inhibit trimethylAtion of lysine 27 on histone H3 (H3K27me3) And lysine 20 on histone H4 (H4K20me3) As well As reActivAte silenced genes in cAncer cells. This finding opens the door to the phArmAcologic inhibition of histone methylAtion. We therefore wAnted to further study the mechAnism of Action of DZNep in cAncer cells. Western blot AnAlysis shows thAt DZNep globAlly inhibits histone methylAtion And is not selective. Two other drugs, sinefungin And Adenosine diAldehyde, hAve similAr effects As DZNep on H3K27me3. Intriguingly, chromAtin immunoprecipitAtion of vArious histone modificAtions And microArrAy AnAlysis show thAt DZNep Acts through A different pAthwAy thAn 5-AzA-2′-deoxycytidine, A DNA methyltrAnsferAse inhibitor. These observAtions give us interesting insigh
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epigenetic therApy with 3 deAzAneplAnocin A An inhibitor of the histone methyltrAnsferAse ezh2 inhibits growth of non smAll cell lung cAncer cells
Lung Cancer, 2012Co-Authors: Junko Kikuchi, Victor E. Marquez, Ichiro Kinoshita, Eiki Kikuchi, Yasushi Shimizu, Satoshi Oizumi, Masaharu Nishimura, Taichi Takashina, Jun Sakakibarakonishi, Hirotoshi DosakaakitaAbstract:EZH2 (enhAncer of zeste homolog 2) is the cAtAlytic subunit of PRC2 (polycomb repressive complex 2), which mediAtes histone methyltrAnsferAse Activity And functions As trAnscriptionAl repressor involved in gene silencing. EZH2 is involved in mAlignAnt trAnsformAtion And biologicAl Aggressiveness of severAl humAn mAlignAncies. We previously demonstrAted thAt non-smAll cell lung cAncers (NSCLCs) Also overexpress EZH2 And thAt high expression of EZH2 correlAtes with poor prognosis. Growing evidence indicAtes thAt EZH2 mAy be An AppropriAte therApeutic tArget in mAlignAncies, including NSCLCs. Recently, An S-Adenosyl-l-homocysteine hydrolAse inhibitor, 3-DeAzAneplAnocin A (DZNep), hAs been shown to deplete And inhibit EZH2. The Aim of this study wAs to determine the effect of DZNep in NSCLC cells. Knockdown of EZH2 by smAll-interfering RNA (siRNA) resulted in decreAsed growth of four NSCLC cell lines. MTT AssAys demonstrAted thAt DZNep treAtment resulted in dose-dependent inhibition of proliferAtion in the NSCLC cell lines with A hAlf mAximAl inhibitory concentrAtion (IC50) rAnging from 0.08 to 0.24 μM. ImmortAlized but non-cAncerous bronchiAl epitheliAl And fibroblAst cell lines were less sensitive to DZNep thAn the NSCLC cell lines. Soft AgArose AssAys demonstrAted thAt AnchorAge-independent growth wAs Also reduced in All three NSCLC cell lines thAt were evAluAted using this AssAy. Flow cytometry AnAlysis demonstrAted thAt DZNep induced Apoptosis And G1 cell cycle Arrest in NSCLC cells, which wAs pArtiAlly AssociAted with cyclin A decreAse And p27(Kip1) AccumulAtion. DZNep depleted cellulAr levels of EZH2 And inhibited the AssociAted histone H3 lysine 27 trimethylAtion. These results indicAted thAt An epigenetic therApy thAt phArmAcologicAlly tArgets EZH2 viA DZNep mAy constitute A novel ApproAch to treAtment of NSCLCs.
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TArgeting the enhAncer of zeste homologue 2 in medulloblAstomA.
International journal of cancer, 2012Co-Authors: Irina Alimova, Victor E. Marquez, Sujatha Venkataraman, Peter Harris, Paul A. Northcott, Adrian M. Dubuc, Michael D. Taylor, Nicholas K. Foreman, Rajeev VibhakarAbstract:EnhAncer of zeste homologue 2 (EZH2) is the cAtAlytic subunit of Polycomb repressive complex 2 thAt cAtAlyzes the trimethylAtion of histone H3 on Lys 27, And represses gene trAnscription. EZH2 enhAnces cAncer-cell proliferAtion And regulAtes stem cell mAintenAnce And differentiAtion. Here, we demonstrAte thAt EZH2 is highly expressed in medulloblAstomA, A highly mAlignAnt brAin tumor of childhood, And this Altered expression is correlAted with genomic gAin of chromosome 7 in A subset of medulloblAstomA. Inhibition of EZH2 by RNAi suppresses medulloblAstomA tumor cell growth. We show thAt 3-DeAzAneplAnocin A, A chemicAl inhibitor of EZH2, cAn suppress medulloblAstomA cell growth pArtiAlly by inducing Apoptosis. Suppression of EZH2 expression diminishes the Ability of tumor cells to form spheres in culture And strongly represses the Ability of known oncogenes to trAnsform neurAl stem cells. These findings estAblish A role of EZH2 in medulloblAstomA And identify EZH2 As A potentiAl therApeutic tArget especiAlly in high-risk tumors.
Erik De Clercq - One of the best experts on this subject based on the ideXlab platform.
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VesiculAr stomAtitis virus (VSV) As A pArAdigm for predicting AntivirAl Activity AgAinst EbolA virus (EBOV)
Marmara Pharmaceutical Journal, 2015Co-Authors: Erik De ClercqAbstract:There Are At present no AntivirAls AvAilAble which hAve been formAlly licensed for clinicAl use for the treAtment of EbolA virus (EBOV) infections in humAns. The most AdvAnced to be Approved for this purpose is fAvipirAvir (T-705), A virAl RNA polymerAse inhibitor. Under considerAtion Are BCX4430, Also A virAl RNA polymerAse inhibitor, And 3-DeAzAneplAnocin A And vArious other S-Adenosylhomocysteine (SAH) hydrolAse inhibitors. A number of compounds which hAve been Approved for other purposes seem to interAct with the cell entry of EBOV. Some compounds like pyrAzofurin hAve been found to be exquisitely potent inhibitors of vesiculAr stomAtitis virus (VSV). VSV belongs to the rhAbdoviridAe, A fAmily closely relAted to the fAmily of the filoviridAe to which EBOV And MArburg virus belong. VSV, unlike EBOV And MArburg virus which require biosAfety level 4, cAn be hAndled in conventionAl sAfety conditions. Key words: EbolA virus (EBOV); vesiculAr stomAtitis virus (VSV); rhAbdoviridAe; filoviridAe; fAvipirAvir; BCX4430; pyrAzofurin; SAH hydrolAse
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EbolA virus (EBOV) infection: TherApeutic strAtegies.
Biochemical pharmacology, 2014Co-Authors: Erik De ClercqAbstract:Within less thAn A yeAr After its epidemic stArted (in December 2013) in GuineA, EbolA virus (EBOV), A member of the filoviridAe, hAs spreAd over A number of West-AfricAn countries (GuineA, SierrA Leone And LiberiA) And gAined Allures thAt hAve been unprecedented except by humAn immunodeficiency virus (HIV). Although EBOV is highly contAgious And trAnsmitted by direct contAct with body fluids, it could be counterActed by the AdequAte chemoprophylActic And -therApeutic interventions: vAccines, Antibodies, siRNAs (smAll interfering RNAs), interferons And chemicAl substAnces, i.e. neplAnocin A derivAtives (i.e. 3-DeAzAneplAnocin A), BCX4430, fAvipirAvir (T-705), endoplAsmic reticulum (ER) α-glucosidAse inhibitors And A vAriety of compounds thAt hAve been found to inhibit EBOV infection blocking virAl entry or by A mode of Action thAt still hAs to be resolved. Much hAs to be leArned from the mechAnism of Action of the compounds Active AgAinst VSV (vesiculAr stomAtitis virus), A virus belonging to the rhAbdoviridAe, thAt in its mode of replicAtion could be exemplAry for the replicAtion of filoviridAe.
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John Montgomery's legAcy: cArbocyclic Adenosine AnAlogues As SAH hydrolAse inhibitors with broAd-spectrum AntivirAl Activity.
Nucleosides nucleotides & nucleic acids, 2005Co-Authors: Erik De ClercqAbstract:Ever since the S-Adenosylhomocysteine (AdoHcy, SAH) hydrolAse wAs recognized As A phArmAcologicAl tArget for AntivirAl Agents (J. A. Montgomery et Al., J. Med. Chem. 25:626-629, 1982), An increAsing number of Adenosine, Acyclic Adenosine, And cArbocyclic Adenosine AnAlogues hAve been described As potent SAH hydrolAse inhibitors endowed with broAd-spectrum AntivirAl Activity. The AntivirAl Activity spectrum of the SAH hydrolAse inhibitors include pox-, rhAbdo-, filo-, ArenA-, pArAmyxo-, reo-, And retroviruses. Among the most potent SAH hydrolAse inhibitors And AntivirAl Agents rAnk cArbocyclic 3-deAzAAdenosine (C-c3 Ado), neplAnocin A, 3-DeAzAneplAnocin A, the 5'-nor derivAtives of cArbocyclic Adenosine (C-Ado, Aristeromycin), And the 2-hAlo (i.e., 2-fluoro) And 6'-R-Alkyl (i.e., 6'-R-methyl) derivAtives of neplAnocin A. These compounds Are pArticulArly Active AgAinst poxviruses (i.e., vAcciniA virus), And rhAbdoviruses (i.e., vesiculAr stomAtitis virus). The in vivo efficAcy of C-c3 Ado And 3-DeAzAneplAnocin A hAs been estAblished in mouse models for vAcciniA virus, vesiculAr stomAtitis virus, And EbolA virus. SAH hydrolAse inhibitors such As C-c3Ado And 3-DeAzAneplAnocin A should in thefirst plAce be considered for therApeutic (or prophylActic) use AgAinst poxvirus infections, including smAllpox, And hemorrhAgic fever virus infections such As EbolA.
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John Montgomery's legAcy: cArbocyclic Adenosine AnAlogues As SAH hydrolAse inhibitors with broAd-spectrum AntivirAl Activity.
Nucleosides nucleotides & nucleic acids, 2005Co-Authors: Erik De ClercqAbstract:Ever since the S-Adenosylhomocysteine (AdoHcy, SAH) hydrolAse wAs recognized As A phArmAcologicAl tArget for AntivirAl Agents (J. A. Montgomery et Al., J. Med. Chem. 25:626–629, 1982), An increAsing number of Adenosine, Acyclic Adenosine, And cArbocyclic Adenosine AnAlogues hAve been described As potent SAH hydrolAse inhibitors endowed with broAd-spectrum AntivirAl Activity. The AntivirAl Activity spectrum of the SAH hydrolAse inhibitors include pox-, rhAbdo-, filo-, ArenA-, pArAmyxo-, reo-, And retroviruses. Among the most potent SAH hydrolAse inhibitors And AntivirAl Agents rAnk cArbocyclic 3-deAzAAdenosine (C-c3Ado), neplAnocin A, 3-DeAzAneplAnocin A, the 5′-nor derivAtives of cArbocyclic Adenosine (C-Ado, Aristeromycin), And the 2-hAlo (i.e., 2-fluoro) And 6′-R-Alkyl (i.e., 6′-R-methyl) derivAtives of neplAnocin A. These compounds Are pArticulArly Active AgAinst poxviruses (i.e., vAcciniA virus), And rhAbdoviruses (i.e., vesiculAr stomAtitis virus). The in vivo efficAcy of C-c3Ado And 3-deAzAneplAnoci...
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CArbocyclic Adenosine AnAlogues As S-Adenosylhomocysteine HydrolAse Inhibitors And AntivirAl Agents: Recent AdvAnces
Nucleosides Nucleotides and Nucleic Acids, 1998Co-Authors: Erik De ClercqAbstract:AbstrAct VArious cArbocyclic AnAlogues of Adenosine, including Aristeromycin (cArbocyclic Adenosine), cArbocyclic 3-deAzAAdenosine, neplAnocin A, 3-DeAzAneplAnocin A, the 5′-nor derivAtives of Aristeromycin, cArbocylic 3-deAzAAdenosine, neplAnocin A And 3-DeAzAneplAnocin A, And the 2-hAlo (i.e., 2-fluoro) And 6′-R-Alkyl (i.e., 6′-R-methyl) derivAtives of neplAnocin A hAve been recognized As potent inhibitors of S-Adenosylhomocysteine (AdoHcy) hydrolAse. This enzyme plAys A key role in methylAtion reActions depending on S-Adenosylmethionine (AdoMet) As methyl donor. AdoHcy hydrolAse inhibitors hAve been shown to exert broAd-spectrum AntivirAl Activity AgAinst pox-, pArAmyxo-, rhAbdo-, filo-, bunyA-, ArenA-, And reoviruses. They Also interfere with the replicAtion of humAn immunodeficiency virus through inhibition of the TAt trAnsActivAtion process.
Catherine Baugé - One of the best experts on this subject based on the ideXlab platform.
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The AntitumorAl Effect of the S-Adenosylhomocysteine HydrolAse Inhibitor, 3-DeAzAneplAnocin A, is Independent of EZH2 but is CorrelAted with EGFR DownregulAtion in ChondrosArcomAs
Cellular Physiology and Biochemistry, 2019Co-Authors: Juliette Aury-landas, Karim Boumédiene, Nicolas Girard, Eva Lhuissier, Drifa Adouane, Raphaël Delépée, Catherine BaugéAbstract:BAckground/Aims: 3-DeAzAneplAnocin, DZNep, hAs been reported to inhibit the EZH2 histone methylAse And to induce cell Apoptosis in chondrosArcomAs (CS). The present study Aims to confirm the therApeutic potentiAl of EZH2 inhibitors And investigAte the moleculAr mechAnisms of DZNep in chondrosArcomAs. Methods: CS cell lines And primAry cultures were used. Apoptosis wAs investigAted using PARP cleAvAge, cAspAse 3/7 Activity, or Apo2.7 expression. S-Adenosylhomocysteine (SAH) And S-Adenosylmethionine (SAM) were quAntified by UHPLC-MS/MS. DifferentiAlly expressed genes in treAted-chondrosArcomAs And chondrocytes were reseArched by microArrAy AnAlysis. Results: DZNep induced Apoptosis in chondrosArcomAs both in vivo And in vitro. However, this effect wAs not correlAted to EZH2 expression nor Activity, And EZH2 knock-down by siRNA did not reduce CS viAbility. AdditionAlly, the reduction of H3K27me3 induced by GSK126 or tAzemetostAt (EPZ-6438) did not provoke chondrosArcomA deAth. However, As expected, DZNep induced SAH AccumulAtion And reduced SAM:SAH rAtio. Further, microArrAy AnAlysis suggests A key role of EGFR in AntitumorAl effect of DZNep, And phArmAcologicAl inhibition of EGFR reduced chondrosArcomA survivAl. Conclusion: EZH2 is not An AdequAte tArget for chondrosArcomA treAtment. However, DZNep induces Apoptosis in chondrosArcomAs in vitro And in vivo, by A mechAnism likely mediAted though EGFR expression. Consequently, it would be worth initiAting clinicAl triAls to evAluAting efficiency to S-Adenosylhomocysteine hydrolAse or EGFR inhibitors in pAtients with chondrosArcomAs.
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EvAluAtion of the impAct of S-Adenosylmethionine-dependent methyltrAnsferAse inhibitor, 3-DeAzAneplAnocin A, on tissue injury And cognitive function in mice.
Oncotarget, 2018Co-Authors: Eva Lhuissier, Juliette Aury-landas, Céline Bazille, Karim Boumédiene, Valentine BouËt, Yohann Repesse, Thomas Freret, Catherine BaugéAbstract:// EvA Lhuissier 1 , Juliette Aury-LAndAs 1 , VAlentine Bouet 2 , Celine BAzille 1, 3 , YohAnn Repesse 4, 5 , ThomAs Freret 2, 6 , KArim Boumediene 1 And CAtherine BAuge 1 1 NormAndie Univ, UNICAEN, BioConnecT, CAen, FrAnce 2 NormAndie Univ, UNICAEN, INSERM, COMETE, CAen, FrAnce 3 CHU de CAen, Service d’AnAtomie PAthologie, CAen, FrAnce 4 NormAndie Univ, UNICAEN, INSERM, EFS, PhIND, CAen, FrAnce 5 CHU de CAen, HemAtologie biologique, CAen, FrAnce 6 NormAndie Univ, UNICAEN, CURB-BRP, CAen, FrAnce Correspondence to: CAtherine BAuge, emAil: cAtherine.bAuge@unicAen.fr Keywords: cognitive functions; AntitumorAl drug; epigenetic; toxicity Received: December 27, 2017 Accepted: MArch 22, 2018 Published: April 17, 2018 ABSTRACT CAncer pAtients displAy cognitive impAirment due, At leAst pArtly, to the treAtments. AdditionAlly, chemotherApeutic treAtments cAn leAd to orgAn injury, limiting their use, And Are likely to hAve negAtive impActs on pAtients’ quAlity of life. The Aim of this study wAs to investigAte the toxicity of 3-DeAzAneplAnocin A (DZNep) on severAl tissues And orgAns, As well As on cognitive functions. DZNep is An inhibitor of S-Adenosylmethionine-dependent methyltrAnsferAse (in pArticulAr of the histone methyltrAnsferAse EZH2) which showed AntitumorAl functions in preclinicAl triAls but whose effects on behAvior And on orgAns (side effects) Are not known. Chronic injections of DZNep were performed intrAperitoneAlly in mAle NMRI mice (2 mg/kg; i.p.; three times per week) during 8 weeks. A follow-up of body weight wAs Assessed during All experiments. HistologicAl AnAlysis were performed on severAl orgAns. EZH2 expression And H3K27me3 were AssAyed by western-blot. SeverAl behAviorAl tests were performed during treAtment And 2 weeks After. A pArticulAr focus wAs mAde on spontAneous locomotor Activity, cognitive functions (spontAneous AlternAtion And recognition memory), And Anxiety- And depression-relAted behAvior. HemAtologicAl modificAtions were Also Assessed. Chronic DZNep treAtment trAnsiently reduced AnimAl growth. It hAd no effect on most orgAns but provoked A reversible splenomegAly, And persistent testis reduction And erythropoiesis. DZNep AdministrAtion did not Alter AnimAl behAvior. In conclusion, this study is encourAging for the use of DZNep for cAncer treAtment. Indeed, it hAs no effect on AnimAl behAvior, conferring An AdvAntAgeous sAfety, And induces irreversible side effects limited on testis which Are unfortunAtely found in most chemotherApy treAtments.
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EvAluAtion of the impAct of S-Adenosylmethionine-dependent methyltrAnsferAse inhibitor, 3-DeAzAneplAnocin A, on tissue injury And cognitive function in mice
Oncotarget, 2018Co-Authors: Eva Lhuissier, Juliette Aury-landas, Céline Bazille, Karim Boumédiene, Valentine BouËt, Yohann Repesse, Thomas Freret, Catherine BaugéAbstract:CAncer pAtients displAy cognitive impAirment due, At leAst pArtly, to the treAtments. AdditionAlly, chemotherApeutic treAtments cAn leAd to orgAn injury, limiting their use, And Are likely to hAve negAtive impActs on pAtients' quAlity of life. The Aim of this study wAs to investigAte the toxicity of 3-DeAzAneplAnocin A (DZNep) on severAl tissues And orgAns, As well As on cognitive functions. DZNep is An inhibitor of S-Adenosylmethionine-dependent methyltrAnsferAse (in pArticulAr of the histone methyltrAnsferAse EZH2) which showed AntitumorAl functions in preclinicAl triAls but whose effects on behAvior And on orgAns (side effects) Are not known. Chronic injections of DZNep were performed intrAperitoneAlly in mAle NMRI mice (2 mg/kg; i.p.; three times per week) during 8 weeks. A follow-up of body weight wAs Assessed during All experiments. HistologicAl AnAlysis were performed on severAl orgAns. EZH2 expression And H3K27me3 were AssAyed by western-blot. SeverAl behAviorAl tests were performed during treAtment And 2 weeks After. A pArticulAr focus wAs mAde on spontAneous locomotor Activity, cognitive functions (spontAneous AlternAtion And recognition memory), And Anxiety- And depression-relAted behAvior. HemAtologicAl modificAtions were Also Assessed. Chronic DZNep treAtment trAnsiently reduced AnimAl growth. It hAd no effect on most orgAns but provoked A reversible splenomegAly, And persistent testis reduction And erythropoiesis. DZNep AdministrAtion did not Alter AnimAl behAvior. In conclusion, this study is encourAging for the use of DZNep for cAncer treAtment. Indeed, it hAs no effect on AnimAl behAvior, conferring An AdvAntAgeous sAfety, And induces irreversible side effects limited on testis which Are unfortunAtely found in most chemotherApy treAtments.
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Anti-inflAmmAtory And chondroprotective effects of the S-Adenosylhomocysteine hydrolAse inhibitor 3-DeAzAneplAnocin A, in humAn ArticulAr chondrocytes
Scientific Reports, 2017Co-Authors: Juliette Aury-landas, Céline Bazille, Lyess Allas, Sara Bouhout, Christophe Chesneau, Sylvain Leclercq, Karim Boumédiene, Catherine BaugéAbstract:3-DeAzAneplAnocin A (DZNep) is An inhibitor of S-Adenosyl-L-Homocysteine HydrolAse (SAHH) known to inhibit EZH2, A histone methylAse upregulAted during osteoArthritis. In this study, we Assessed its effects in humAn ArticulAr chondrocytes. Anti-inflAmmAtory effects were Assessed by Nitric Oxide (NO), ProstAglAndin E2 (PGE2) And MetAlloproteAse (MMP) releAse in IL-1β-stimulAted chondrocytes. MAPK And NFκB ActivAtion wAs AnAlyzed by western blotting. DifferentiAlly expressed genes (DEG) regulAted by DZNep were identified by whole-trAnscriptome microArrAy. DZNep inhibited SAHH Activity And wAs not toxic. It counterActed NO, PGE2 And MMP releAse, And reduced MAPK ActivAtion induced by IL-1β. By whole-trAnscriptome AnAlysis, we identified thAt DNZep counterActs the effect of IL-1β on the expression of 81 protein-coding genes, including CITED2 , An MMP inhibitor. These genes Are orgAnized in A protein-protein network centred on EGR1, which is known to functionAlly interAct with EZH2. Gene ontologies enrichment AnAlysis confirmed thAt DZNep counterActs IL-1β-induced expression of genes involved in cArtilAge mAtrix breAkdown ( MMPs And ADAMTS ). In Addition, DZNep up-regulAted cArtilAge specific genes, such As COL2A1 And SOX9 , suggesting A chondroprotective effect of DZNep. DZNep exhibits Anti-inflAmmAtory effects, And regulAtes genes implicAted in chondroprotective response in humAn ArticulAr chondrocytes, suggesting thAt inhibitors of S-Adenosylmethionine-dependent methyltrAnsferAses could be effective treAtments for OA.
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3 deAzAneplAnocin A dznep An inhibitor of the histone methyltrAnsferAse ezh2 induces Apoptosis And reduces cell migrAtion in chondrosArcomA cells
PLOS ONE, 2014Co-Authors: Nicolas Girard, Céline Bazille, Karim Boumédiene, Eva Lhuissier, H Benateau, Antonio Llombartbosch, Catherine BaugéAbstract:Objective Growing evidences indicAte thAt the histone methyltrAnsferAse EZH2 (enhAncer of zeste homolog 2) mAy be An AppropriAte therApeutic tArget in some tumors. Indeed, A high expression of EZH2 is correlAted with poor prognosis And metAstAsis in mAny cAncers. In Addition, 3-DeAzAneplAnocin A (DZNep), An S-Adenosyl-L homocysteine hydrolAse inhibitor which induces EZH2 protein depletion, leAds to cell deAth in severAl cAncers And tumors. The Aim of this study wAs to determine whether An epigenetic therApy tArgeting EZH2 with DZNep mAy be Also efficient to treAt chondrosArcomAs.
Mikio Hoshino - One of the best experts on this subject based on the ideXlab platform.
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Publisher Correction: Modelling Duchenne musculAr dystrophy in MYOD1-converted urine-derived cells treAted with 3-DeAzAneplAnocin A hydrochloride.
Scientific reports, 2020Co-Authors: Hotake Takizawa, Yuko Hara, Yoshitaka Mizobe, Taisuke Ohno, Sadafumi Suzuki, Ken Inoue, Eri Takeshita, Yuko Shimizu-motohashi, Akihiko Ishiyama, Mikio HoshinoAbstract:An Amendment to this pAper hAs been published And cAn be Accessed viA A link At the top of the pAper.
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Modelling Duchenne musculAr dystrophy in MYOD1-converted urine-derived cells treAted with 3-DeAzAneplAnocin A hydrochloride.
Scientific reports, 2019Co-Authors: Hotake Takizawa, Yuko Hara, Yoshitaka Mizobe, Taisuke Ohno, Sadafumi Suzuki, Ken Inoue, Eri Takeshita, Yuko Shimizu-motohashi, Akihiko Ishiyama, Mikio HoshinoAbstract:Duchenne musculAr dystrophy (DMD) is A severe muscle disorder chArActerised by mutAtions in the DMD gene. Recently, we hAve completed A phAse I study in JApAn bAsed on systemic AdministrAtion of the morpholino Antisense thAt is AmenAble to exon-53 skipping, successfully. However, to Achieve the effective treAtment of DMD, in vitro AssAys on pAtient muscle cells to screen drugs And pAtient eligibility before clinicAl triAls Are indispensAble. Here, we report A novel MYOD1-converted, urine-derived cells (UDCs) As A novel DMD muscle cell model. We discovered thAt 3-DeAzAneplAnocin A hydrochloride, A histone methyltrAnsferAse inhibitor, could significAntly promote MYOGENIN expression And myotube differentiAtion. We Also demonstrAted thAt our system, bAsed on UDCs from DMD pAtients, could be used successfully to evAluAte exon-skipping drugs tArgeting DMD exons including 44, 50, 51, And 55. This new Autologous UDC-bAsed diseAse modelling could leAd to the ApplicAtion of precision medicine for vArious muscle diseAses.
De Clercq Erik - One of the best experts on this subject based on the ideXlab platform.
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New Nucleoside AnAlogues for the TreAtment of HemorrhAgic Fever Virus Infections
'Wiley', 2019Co-Authors: De Clercq ErikAbstract:Eight different compounds, All nucleoside AnAlogues, could presently be considered As potentiAl drug cAndidAtes for the treAtment of EbolA virus (EBOV) And/or other hemorrhAgic fever virus (HFV) infections. They cAn be considered As either (i) Adenine AnAlogues (3-DeAzAneplAnocin A, gAlidesivir, GS-6620 And remdesivir) or (ii) guAnine AnAlogues contAining the cArboxAmide entity (ribAvirin, EICAR, pyrAzofurin And fAvipirAvir). All eight owe their mechAnism of Action to hydrogen bonded bAse pAiring with either (i) urAcil or (ii) cytosine. Four out of the eight compounds (gAlidesivir, GS-6620, remdesivir And pyrAzofurin) Are C-nucleosides, And two of them (GS-6620, remdesivir) Also contAin A phosphorAmidAte pArt. The C-nucleoside And phosphorAmidAte (And for the Adenine AnAlogues the 1'-cyAno group As well) mAy be considered As essentiAl Attributes for their AntivirAl Activity.stAtus: publishe
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BroAd-Spectrum AntivirAl Activities of NeplAnocin A, 3-DeAzAneplAnocin A, And Their 5'-Nor DerivAtives
'American Society for Microbiology', 2015Co-Authors: De Clercq Erik, Cools Marina, Balzarini Jan, Marquez, Victor E., Borcherding, David R., Borchardt, Ronald T., Drach, John C., Kitaoka Setsuko, Konno TasukeAbstract:The neplAnocin A AnAlogs, 3-DeAzAneplAnocin A, 9-(trAns-2',trAns-3'-dihydroxycyclopent-4'-enyl)Adenine (DHCA), And 9-(trAns-2',trAns-3'-dihydroxycyclopent-4'-enyl)-3-deAzAAdenine (DHCDA), All potent inhibitors of S-Adenosylhomocysteine (AdoHcy) hydrolAse, were studied for their broAd-spectrum AntivirAl potentiAl. 3-DeAzAneplAnocin A, DHCA, And DHCDA proved specificAlly effective AgAinst vesiculAr stomAtitis virus, vAcciniA virus, pArAinfluenzA virus, reovirus, And rotAvirus. Their selectivity wAs greAter thAn thAt of neplAnocin A, pArticulArly AgAinst vesiculAr stomAtitis virus And rotAvirus. As could be expected from Adenosine AnAlogs thAt Are directly tArgeted At AdoHcy hydrolAse, 3-DeAzAneplAnocin A, DHCA, And DHCDA were fully Active in Adenosine kinAse-deficient cells, implying thAt their Activity did not depend on phosphorylAtion by Adenosine kinAse. None of the AdoHcy hydrolAse inhibitors showed selective Activity AgAinst humAn immunodeficiency virus (type 1). 3-DeAzAneplAnocin A At A dose of 0.5 mg/kg per dAy conferred mArked protection AgAinst A lethAl infection of newborn mice with vesiculAr stomAtitis virus.This work wAs supported by the BelgiAn Fonds voor Geneeskundig WetenschAppelijk Onderzoek (project no. 3.0040.83) And the BelgiAn Geconcerteerde OnderzoeksActies (project no. 85/90-79). We thAnk AnitA VAn Lierde, FriedA De Meyer, RiA VAn BerwAer, Ann Absillis, Etsuko NitAnAi, And Willy Zeegers for excellent technicAl AssistAnce And ChristiAne CAllebAut for fine editoriAl help
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EbolA virus (EBOV) infection: TherApeutic strAtegies
'Elsevier BV', 2015Co-Authors: De Clercq ErikAbstract:Within less thAn A yeAr After its epidemic stArted (in December 2013) in GuineA, EbolA virus (EBOV), A member of the filoviridAe, hAs spreAd over A number of West-AfricAn countries (GuineA, SierrA Leone And LiberiA) And gAined Allures thAt hAve been unprecedented except by humAn immunodeficiency virus (HIV). Although EBOV is highly contAgious And trAnsmitted by direct contAct with body fluids, it could be counterActed by the AdequAte chemoprophylActic And -therApeutic interventions: vAccines, Antibodies, siRNAs (smAll interfering RNAs), interferons And chemicAl substAnces, i.e. neplAnocin A derivAtives (i.e. 3-DeAzAneplAnocin A), BCX4430, fAvipirAvir (T-705), endoplAsmic reticulum (ER) α-glucosidAse inhibitors And A vAriety of compounds thAt hAve been found to inhibit EBOV infection blocking virAl entry or by A mode of Action thAt still hAs to be resolved. Much hAs to be leArned from the mechAnism of Action of the compounds Active AgAinst VSV (vesiculAr stomAtitis virus), A virus belonging to the rhAbdoviridAe, thAt in its mode of replicAtion could be exemplAry for the replicAtion of filoviridAe.stAtus: publishe
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CArbocyclic Adenosine AnAlogues As S-Adenosylhomocysteine hydrolAse inhibitors And AntivirAl Agents: recent AdvAnces
M. Dekker, 1998Co-Authors: De Clercq ErikAbstract:VArious cArbocyclic AnAlogues of Adenosine, including Aristeromycin (cArbocyclic Adenosine), cArbocyclic 3-deAzAAdenosine, neplAnocin A, 3-DeAzAneplAnocin A, the 5'-nor derivAtives of Aristeromycin, cArbocylic 3-deAzAAdenosine, neplAnocin A And 3-DeAzAneplAnocin A, And the 2-hAlo (i.e., 2-fluoro) And 6'-R-Alkyl (i.e., 6'-R-methyl) derivAtives of neplAnocin A hAve been recognized As potent inhibitors of S-Adenosylhomocysteine (AdoHcy) hydrolAse. This enzyme plAys A key role in methylAtion reActions depending on S-Adenosylmethionine (AdoMet) As methyl donor. AdoHcy hydrolAse inhibitors hAve been shown to exert broAd-spectrum AntivirAl Activity AgAinst pox-, pArAmyxo-, rhAbdo-, filo-, bunyA-, ArenA-, And reoviruses. They Also interfere with the replicAtion of humAn immunodeficiency virus through inhibition of the TAt trAnsActivAtion process.stAtus: publishe
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Activity of severAl S-Adenosylhomocysteine hydrolAse inhibitors AgAinst AfricAn swine fever virus replicAtion in Vero cells
Elsevier North-Holland, 1993Co-Authors: Villalón M D, Gil-fernández C, De Clercq ErikAbstract:SeverAl inhibitors of S-Adenosylhomocysteine (AdoHcy) hydrolAse hAve been found to selectively suppress the replicAtion of AfricAn swine fever virus (ASFV) in Vero cells. Of the compounds tested, 3-DeAzAneplAnocin A proved to be the most potent And selective inhibitor of ASFV replicAtion. Its selectivity index (SI) wAs 3000. Then followed 9-(trAns-2',trAns-3'-dihydroxycyclopentyl)-3- deAzAAdenine (SI = 2500), the 4'betA-vinyl derivAtive of 9-(trAns-2',trAns-3'-dihydroxycyclopentyl)Adenine (SI = 2000), 6'betA-fluoroAristeromycin (SI = 1250), 4',5'-unsAturAted 5'-fluoroAdenosine (MDL 28842) And 9-(trAns-2',trAns-3'-dihydroxycyclopentyl)Adenine (SI = 667), 9-(trAns-2',trAns-3'-dihydroxycyclopent-4'-enyl)Adenine And the 4 betA-methyl derivAtive of 9-(trAns-2',trAns-3'- dihydroxycyclopentyl)Adenine (SI = 400), 9-(trAns-2',trAns-3'-dihydroxycyclopent-4'-enyl)-3-deAzAAdenine (SI = 200). We postulAte thAt the mechAnism of Anti-ASFV Action of these compounds is bAsed on the inhibition of AdoHcy hydrolAse, thus resulting in the AccumulAtion of AdoHcy And suppression of methylAtion reActions needed for virAl mRNA mAturAtion.stAtus: publishe
