PRIMA-1Met induces myeloma cell death independently of p53 by impairing the GSH/ROS balance
Menée sur des lignées cellulaires, sur des échantillons prélevés sur des patients atteints d'un myélome multiple et à l'aide de xénogreffes, cette étude française évalue l'activité antitumorale d'une molécule appelée PRIMA-1Met
The aim of this study was to assess the efficiency of PRIMA-1Met in inducing myeloma cell death using 27 human myeloma cell lines (HMCLs) and 23 primary samples. Measuring the LD50 of HMCLs revealed that HMCLs displayed heterogeneous sensitivity, with an LD50 ranging from 4 µM to more than 200 µM. The sensitivity of HMCLs did not correlate with myeloma genomic heterogeneity or TP53 status, and PRIMA-1Met did not induce or increase expression of the p53 target genes CDKN1A or TNFRSF10B/DR5. However, PRIMA-1Met increased expression of NOXA in a p53-independent manner and NOXA silencing decreased PRIMA1Met-induced cell death. PRIMA-1Met depleted GSH content and induced ROS production. The expression of Glutathione synthetase correlated with PRIMA-1Met LD50 values and we showed that GSH decrease mediated by GSS silencing or by BSO, an irreversible inhibitor of γ-Glutamylcysteine synthetase, increased PRIMA-1Met-induced cell death and overcame PRIMA-1Met resistance. PRIMA-1Met (10 µM) induced cell death in 65% of primary cells independently of the presence of del17p, did not increase DR5 expression, arguing against an activation of p53 pathway, and synergized with BSO in all samples. Finally, we showed in mouse TP53neg JJN3-xenograft model that PRIMA-1Met inhibited myeloma growth and synergized with BSO in vivo.
Blood 2014