title: Iron chelators induce autophagic cell death in multiple myeloma cells.
abstract: We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma.
authors.affiliation: Jane Ann Nohl Division of Hematology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. Electronic address: vpullarkat@coh.org.
authors.forename: Vinod
authors.initials: V
authors.lastname: Pullarkat
authors.affiliation: Jane Ann Nohl Division of Hematology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Medical Oncology, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Cecile
authors.initials: C
authors.lastname: Donohue
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Vicky N
authors.initials: VN
authors.lastname: Yamamoto
authors.affiliation: Jane Ann Nohl Division of Hematology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tomassetti
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Department of Medical Oncology, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077588:Deferasirox; D003676:Deferoxamine / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D014230:Triazoles; D003676:Deferoxamine; D000077588:Deferasirox
keywords: Autophagy; Deferasirox; Deferoxamine; Iron chelation; Multiple myeloma; mTOR; p70S6 kinase