Small Molecule Therapeutics PRIMA-1/APR-246 Displays High Antitumor Activity in Multiple Myeloma By Induction of p73 and Noxa

Targeting p53 by the small-molecule PRIMA-1/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1–induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1 alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, andamousexenograftmodel. Results of our study showed that PRIMA-1 decreased theviability of multiplemyeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells. Treatment of multiple myeloma cells with PRIMA-1 resulted in induction of apoptosis, inhibition of colony formation, andmigration. PRIMA-1 restoredwild-type conformation ofmutant p53 and induced activation of p73 upregulating Noxa and downregulating Mcl-1 without significant modulation of p53 level. siRNAmediated silencing of p53 showed a little effect on apoptotic response of PRIMA-1, whereas knockdown of p73 led to substantial attenuation of apoptotic activity inmultiplemyeloma cells, indicating that PRIMA-1– induced apoptosis is, at least in part, p73–dependent. Importantly, PRIMA-1 delayed tumor growth and prolonged survival of mice bearing multiple myeloma tumor. Furthermore, combined treatment of PRIMA1 with dexamethasone or doxorubicin displayed synergistic effects in bothmultiple myeloma cell lines and primary multiple myeloma samples. Consistent with our in vitro observations, cotreatment with PRIMA-1 and dexamethasone resulted in enhanced antitumor activity in vivo. Our study for the first time shows antimyeloma activity of PRIMA-1 and provides the rationale for its clinical evaluation in patients with multiple myeloma, including the high-risk group with p53 mutation/deletion. Mol Cancer Ther; 12(11);