2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one and Multiple-Myeloma

Targeting p53 by the small-molecule PRIMA-1(Met)/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1(Met)-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(Met) alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1(Met) decreased the viability of multiple myeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells. Treatment of multiple myeloma cells with PRIMA-1(Met) resulted in induction of apoptosis, inhibition of colony formation, and migration. PRIMA-1(Met) restored wild-type conformation of mutant p53 and induced activation of p73 upregulating Noxa and downregulating Mcl-1 without significant modulation of p53 level. siRNA-mediated silencing of p53 showed a little effect on apoptotic response of PRIMA-1(Met), whereas knockdown of p73 led to substantial attenuation of apoptotic activity in multiple myeloma cells, indicating that PRIMA-1(Met)-induced apoptosis is, at least in part, p73-dependent. Importantly, PRIMA-1(Met) delayed tumor growth and prolonged survival of mice bearing multiple myeloma tumor. Furthermore, combined treatment of PRIMA-1(Met) with dexamethasone or doxorubicin displayed synergistic effects in both multiple myeloma cell lines and primary multiple myeloma samples. Consistent with our in vitro observations, cotreatment with PRIMA-1(Met) and dexamethasone resulted in enhanced antitumor activity in vivo. Our study for the first time shows antimyeloma activity of PRIMA-1(Met) and provides the rationale for its clinical evaluation in patients with multiple myeloma, including the high-risk group with p53 mutation/deletion.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Dexamethasone; DNA-Binding Proteins; Doxorubicin; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, SCID; Multiple Myeloma; Neoplasms, Experimental; Nuclear Proteins; Proto-Oncogene Proteins c-bcl-2; Quinuclidines; Tumor Protein p73; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays