Deazaneplanocin a Is a Promising Drug to Kill Multiple Myeloma Cells in Their Niche

Jérémie Gaudichon (1) , Francesco Milano (1) , Julie Cahu (1) , Laetitia Dacosta (2) , Anton C. Martens (3) , Jack-Michel Renoir (2) , Brigitte Sola (1)

1 MILPAT - Microenvironnement cellulaire et pathologie
2 U749 - Recepteurs et Signalisation des Interleukines
3 University Medical Center [Utrecht]

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), acomponent 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 celldeath was not mediated through its effect on EZH2 and the trimethylation on lysine 27 of histone H3 (H3K27me3). DZNeplikely acted through non-epigenetic mechanisms in myeloma cells.In vivo, in xenograft models, andin vitroDZNep showedpotent antimyeloma activity alone or in combination with bortezomib. These preclinical data let us to envisage newtherapeutic strategies for myeloma.

Domaines: Cancer; Hématologie; Pharmacologie

Jérémie Gaudichon, Francesco Milano, Julie Cahu, Laetitia Dacosta, Anton C. Martens, et al.. Deazaneplanocin a Is a Promising Drug to Kill Multiple Myeloma Cells in Their Niche. PLoS ONE, 2014, 9 (9), pp.e107009. ⟨10.1371/journal.pone.0107009⟩. ⟨hal-01762007⟩