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PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance.
- Source :
-
Blood [Blood] 2014 Sep 04; Vol. 124 (10), pp. 1626-36. Date of Electronic Publication: 2014 Jul 08. - Publication Year :
- 2014
-
Abstract
- The aim of this study was to assess the efficiency of p53 reactivation and induction of massive apoptosis (PRIMA-1(Met)) in inducing myeloma cell death, using 27 human myeloma cell lines (HMCLs) and 23 primary samples. Measuring the lethal dose (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-1(Met) did not induce or increase expression of the p53 target genes CDKN1A or TNFRSF10B/DR5. However, PRIMA-1(Met) increased expression of NOXA in a p53-independent manner, and NOXA silencing decreased PRIMA1(Met)-induced cell death. PRIMA-1(Met) depleted glutathione (GSH) content and induced reactive oxygen species production. The expression of GSH synthetase correlated with PRIMA-1(Met) LD50 values, and we showed that a GSH decrease mediated by GSH synthetase silencing or by and L-buthionine sulphoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, increased PRIMA-1(Met)-induced cell death and overcame PRIMA-1(Met) resistance. PRIMA-1(Met) (10 μM) induced cell death in 65% of primary cells independent of the presence of del17p; did not increase DR5 expression, arguing against an activation of p53 pathway; and synergized with L-buthionine sulphoximine in all samples. Finally, we showed in mouse TP53(neg) JJN3-xenograft model that PRIMA-1(Met) inhibited myeloma growth and synergized with L-buthionine sulphoximine in vivo.<br /> (© 2014 by The American Society of Hematology.)
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Cell Death drug effects
Cells, Cultured
Female
Humans
Mice
Mice, SCID
Multiple Myeloma drug therapy
Multiple Myeloma metabolism
Quinuclidines therapeutic use
Signal Transduction drug effects
Tumor Suppressor Protein p53 physiology
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Apoptosis drug effects
Glutathione metabolism
Multiple Myeloma pathology
Quinuclidines pharmacology
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 124
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 25006124
- Full Text :
- https://doi.org/10.1182/blood-2014-01-548800