PRIMA-1Met/APR-246 displays high anti-tumor activity in multiple myeloma by induction of p73 and Noxa
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'une petite molécule appeléé PRIMA-1Met, en combinaison avec la doxorubicine ou la dexaméthasone, pour le traitement d'un myélome multiple, notamment chez les patients présentant une mutation ou une délétion du gène p53
Targeting p53 by the small molecule PRIMA-1Met/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1Met-induced apoptosis is not completely understood and its effect on multiple myeloma (MM) cells is unknown. In this study we evaluated anti-tumor effect of PRIMA-1Met alone or its combination with current anti-myeloma agents in MM cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1Met decreased the viability of MM cells irrespective of p53 status with limited cytotoxicity toward normal hematopoietic cells. Treatment of MM cells with PRIMA-1Met resulted in induction of apoptosis, inhibition of colony formation and migration. PRIMA-1Met restored wild type conformation of mutant p53 and induced activation of p73 up-regulating Noxa and down-regulating Mcl-1 without significant modulation of p53 level. siRNA mediated silencing of p53 showed a little effect on apoptotic response of PRIMA-1Met, whereas knockdown of p73 led to substantial attenuation of apoptotic activity in MM cells, indicating that PRIMA-1Met-induced apoptosis is, at least in part, p73-dependent. Importantly, PRIMA-1Met delayed tumor growth and prolonged survival of mice bearing MM tumor. Furthermore, combined treatment of PRIMA-1Met with dexamethasone or doxorubicin displayed synergistic effects in both MM cell lines and primary MM samples. Consistent with our in vitro observations, co-treatment with PRIMA-1Met and dexamethasone resulted in enhanced anti-tumor activity in vivo. Our study for the first time demonstrates anti-myeloma activity of PRIMA-1Met and provides the rationale for its clinical evaluation in MM patients including the high risk group with p53 mutation/deletion.
http://mct.aacrjournals.org/content/early/2013/09/12/1535-7163.MCT-12-1166.abstract