title: Deazaneplanocin a is a promising drug to kill multiple myeloma cells in their niche.
abstract: Tumoral plasma cells has retained stemness features and in particular, a polycomb-silenced gene expression signature. Therefore, epigenetic therapy could be a mean to fight for multiple myeloma (MM), still an incurable pathology. Deazaneplanocin A (DZNep), a S-adenosyl-L-homocysteine hydrolase inhibitor, targets enhancer of zest homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2) and is capable to induce the death of cancer cells. We show here that, in some MM cell lines, DZNep induced both caspase-dependent and -independent apoptosis. However, the induction of cell death was not mediated through its effect on EZH2 and the trimethylation on lysine 27 of histone H3 (H3K27me3). DZNep likely acted through non-epigenetic mechanisms in myeloma cells. In vivo, in xenograft models, and in vitro DZNep showed potent antimyeloma activity alone or in combination with bortezomib. These preclinical data let us to envisage new therapeutic strategies for myeloma.
authors.affiliation: Equipe Associée 4652, Université de Caen, Normandie Univ, Caen, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Gaudichon
authors.affiliation: Equipe Associée 4652, Université de Caen, Normandie Univ, Caen, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Milano
authors.affiliation: Equipe Associée 4652, Université de Caen, Normandie Univ, Caen, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Cahu
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U749, Institut Gustave Roussy, Villejuif, France.
authors.forename: Lætitia
authors.initials: L
authors.lastname: DaCosta
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Anton C
authors.initials: AC
authors.lastname: Martens
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U749, Institut Gustave Roussy, Villejuif, France.
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir
authors.affiliation: Equipe Associée 4652, Université de Caen, Normandie Univ, Caen, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sola
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004347:Drug Interactions; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology; D053668:Syndecan-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D053668:Syndecan-1; C048460:3-deazaneplanocin; D000069286:Bortezomib; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D020169:Caspases; D000241:Adenosine