title: Dexamethasone-induced oxidative stress enhances myeloma cell radiosensitization while sparing normal bone marrow hematopoiesis.
abstract: Dexamethasone (Dex) and radiation therapy are established modalities in multiple myeloma. In this study, we propose a novel combination of Dex plus radiation that shows superior clonogenic cell killing and apoptosis of myeloma cells and selectively eliminates myeloma cells when cocultured with bone marrow stromal cells (BMSCs). Dex was found to inhibit the release of interleukin-6 from irradiated BMSCs, which is an established myeloma cell proproliferative cytokine. In 5TGM1 model, the combination of Dex with skeletal targeted radiotherapy (153-Sm-EDTMP) prolonged median survival time and inhibited radiation-induced myelosuppression. A two-cycle treatment of Dex plus 153-Sm-EDTMP was well tolerated and further improved median survival time. Mechanistically, Dex increased superoxide and hydrogen peroxide production and augmented radiation-induced oxidative stress and cell death of myeloma cells. In contrast, Dex inhibited radiation-induced increase in pro-oxidant levels and enhanced the clonogenic survival in normal hematopoietic stem and progenitor cells. Treatment with either N-acetylcysteine or the combination of polyethylene glycol (PEG)-conjugated copper, zinc-superoxide dismutase, and PEG-catalase significantly protected myeloma cells from Dex-induced clonogenic death. Overall, these results demonstrate that Dex in combination with radiotherapy enhances the killing of myeloma cells while protecting normal bone marrow hematopoiesis through a mechanism that involves selective increases in oxidative stress.
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242-1181, USA.
authors.forename: Soumen
authors.initials: S
authors.lastname: Bera
authors.forename: Suzanne
authors.initials: S
authors.lastname: Greiner
authors.forename: Amit
authors.initials: A
authors.lastname: Choudhury
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.forename: Apollina
authors.initials: A
authors.lastname: Goel
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D003131:Combined Modality Therapy; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000528:radiation effects; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000532:radiotherapy*; D018384:Oxidative Stress; D010950:Plasma Cells / Q000187:drug effects; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D013482:Superoxide Dismutase / Q000378:metabolism / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D015850:Interleukin-6; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D003907:Dexamethasone; D013482:Superoxide Dismutase; D000111:Acetylcysteine