Background The aim of this study was to evaluate the efficacy of the p53-reactivating medicines RITA and nutlin3a in killing myeloma cells. of myeloma cells. The apoptosis that was induced by (R)-P7C3-Ome RITA was not related to the status of the cell lines or the del17p status of the primary samples (p = 0.52 and p = 0.80 respectively) and RITA did not commonly increase the expression level of p53 (R)-P7C3-Ome or p53 focuses on (Noxa p21 Bax (R)-P7C3-Ome or DR5) in sensitive cells. Moreover silencing of p53 in two cell lines failed to inhibit apoptosis that was induced by RITA which confirmed that RITA-induced apoptosis in myeloma cells was p53 self-employed. In contrast apoptosis induced by nutlin3a was directly linked to the status of the cell lines and main samples (p < 0.001 and p = 0.034 respectively) and nutlin3a increased the level of p53 and p53 focuses on inside a p53-dependent manner. Finally we showed that a nutlin3a-induced DR5 increase (≥1.2-fold increase) was a specific and sensitive marker (p < 0.001) for any weak incidence of 17p deletion within the samples (≤19%). Summary These data display that RITA in contrast to nutlin3a efficiently induced apoptosis inside a subset of MM cells individually of p53. The findings and could become of interest for individuals having a 17p deletion who are resistant to current therapies. is the most frequently mutated gene in cancers and those mutations are associated with resistance to therapy in numerous cancers including hematologic malignancies such as multiple myeloma (MM) [2 3 Although MM is an incurable plasma cell malignancy treatments have progressed in the past decade . Over the last 15?years individuals at diagnosis having a deletion of the short arm of chromosome 17 del(17p) which overlaps the locus (17p13) have been shown to have a shorter survival time that is independent of the treatment regimens [4-8]. Moreover the rate of recurrence of del(17p) raises with successive relapses suggesting selection and resistance of del(17p)?+?cells to therapy . The incidence of the mutation on the remaining allele is high in individuals with del(17p) which suggests that is the target gene of the chromosomal deletion . Therapies that either bypass the defective p53 pathway or reactivate the p53 protein in cells expressing a mutant protein are needed. Molecules that can reactivate cell death in p53-mutant cells inside a p53-dependent manner have been selected based on their ability to either destroy the cells (phenotypic testing) or bind to the mutated p53 protein and restore a functional p53 conformation (biochemical testing) [11 12 Therefore several molecules such as PRIMA RITA and CP-31398 have been selected and will be evaluated in clinical tests [11-15]. RITA (Reactivating p53 and inducing tumor apoptosis) was isolated from a chemical library by its ability to get rid of the HCT116 cell collection and spare its variant HCT116 abnormalities found in individuals (e.g. chromosome 17p deletion different point mutations exon deletion) which allows us to provide an accurate preclinical evaluation. The effectiveness of RITA was compared with that of nutlin3a which reactivates the p53 pathway and only induces cell death in status. Methods Human being myeloma cell lines (HMCLs) and main myeloma cells All HMCLs used in this article were previously extensively characterized [21 23 The HMCLs (R)-P7C3-Ome BCN MDN NAN-1 -3 -6 -7 -8 SBN and XG-1 -2 -3 -5 -6 -7 -11 were derived in (R)-P7C3-Ome the Nantes or Montpellier laboratories in the presence of IL-6. KMS-11 KMS12-BM KMS12-PE and KMM1 were kindly provided by Dr Otsuki (Kawasaki Medical School Kurashiki Japan). ANBL-6 JJN3 JIM3 Karpas620 and MM1S HMCLs were kindly provided by Dr Jelinek (Rochester MN USA) by Dr. Vehicle Riet (Brussels Belgium) by Dr MacLennan (Birmingham UK) by Dr Karpas (Cambridge UK) and by Dr S. Rosen (Chicago IL USA) respectively. AMO1 LP1 L363 NCI-H929 SKMM2 U266 and OPM2 were purchased from DSMZ (Braunsweig Germany) and RPMI8226 was purchased from ATTC (USA). ANBL-6 ACAD9 BCN MDN NAN SBN and XG cells were cultured in RPMI1640 comprising 5% FCS in the presence of 3?ng/ml IL6 (Novartis Pharmaceuticals Basel Switzerland). Blood or bone marrow samples from individuals with MM at analysis or relapse were collected after educated consent in the Division of Hematology in the University or college Hospital of Nantes or in the Intergroupe Francophone du Myélome (honest authorization n° DC-2011-1399 Pr Rodat). Plasma cells were obtained.