Biological Pathways and In Vivo Anti-Tumor Activity Induced by Atiprimod in Multiple Myeloma (MM).

Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is a novel orally bio-available agent with anti-inflammatory properties. Although its in vitro anti-MM activity have been previously reported, here we have investigated molecular changes induced by Atiprimod as well as its in vivo activity in murine models of MM. Atiprimod inhibits in vitro growth and survival of IL-6 dependent as well as independent MM cell-lines in a time- and dose-dependent manner. Evaluation of changes in gene expression profile following treatment with Atiprimod identified down-regulation of genes involved in adhesion, cell-signalling, cell-cycle and BMP pathways and up-regulation of genes implicated in apoptosis and bone metabolism. The signalling pathway analysis identified the integrin, TGF-beta and FGF signaling as well as Wnt/b-catenin, IGF1 and cell cycle regulation networks as being most modulated by Atiprimod treatment. Next, we evaluated its in vivo activity in three different murine models of MM. A xenograft model bearing subcutaneous MM cells confirmed in vivo the anti-MM activity of Atiprimod and established its dose-response activity; a model based on engraftment of human fetal bone chip implanted in SCID mice (SCID-hu) with INA-6 cells, confirmed its ability to overcome the protective effects of the bone marrow milieu on MM cell growth, survival and drug resistance; and a SCID-hu model engrafted with primary patient MM cells confirmed its activity in the context of primary human disease recapitulating the clinical condition. Finally, we observed reduced number of osteoclasts, following Atiprimod treatment, compared to control bone samples confirming its beneficial effects on bone remodelling. Taken together, these data demonstrate the in vitro and in vivo anti-tumor activity of Atiprimod and delineate potential molecular targets triggered by this agent, providing a preclinical rational for its clinical evaluation in MM.