Fenretinide targets the side population in myeloma cell line NCI-H929 and potentiates the efficacy of antimyeloma with bortezomib and dexamethasone regimen

Abstract

Side population (SP) cells, a subset of enriched tumor initiating cells, have been demonstrated to have stem cell-like properties in multiple myeloma (MM) by us as well as other previous studies. A lack of agents targeting tumor initiating cells, however, represents a challenge in the treatment of MM. Previously, fenretinide, a well-tolerated vitamin A derivative, has been shown to exert effect on leukemic stem cells, but its actions against myeloma stem-like cells are still unknown. In this study, the effects of fenretinide on myeloma stem-like cells characteristic was comprehensively examined in SP and non-SP (MP) cells of NCI-H929 cell sorted by flow cytometry-based on Hoechst 33342 stain. We find that fenretinide is capable of eradicating MM SP and MP cells, but not normal bone marrow mononuclear cells (BMMCs) at physiologically achievable concentrations. Fenretinide alone exerted a selective cytotoxic effect on MM SP cells, as well as in combination with bortezomib and dexamethasone. In particular, SP cells were highly sensitive to fenretinide, and in combination with bortezomib and dexamethasone in colony formation and apoptosis assays. Accordingly, the apparent fenretinide-induced-apoptosis was linked to the rapid generation of reactive oxygen species (ROS). Therefore, we propose that fenretinide is a potent agent that targets tumor initiating cells and may be a promising therapeutic agent in MM treatment.