Fenretinide targets the side population in myeloma cell line NCI-H929 and potentiates the efficacy of antimyeloma with bortezomib and dexamethasone regimen.
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.
Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
Wenqing
W
Yan
Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
Juan
J
Du
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
Yanzhi
Y
Du
Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
Honglei
H
Pu
Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
Shuyan
S
Liu
Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
Jie
J
He
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
Ji
J
Zhang
Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China. Electronic address: houjian167@sohu.com.
Jian
J
Hou
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D017313:Fenretinide / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D017382:Reactive Oxygen Species; D058985:Side-Population Cells / Q000187:drug effects* / Q000473:pathology
D017382:Reactive Oxygen Species; D017313:Fenretinide; D000069286:Bortezomib; D003907:Dexamethasone
Bortezomib; Dexamethasone; Fenretinide; Multiple myeloma; Side population