title: Bortezomib and IL-12 produce synergetic anti-multiple myeloma effects with reduced toxicity to natural killer cells.
abstract: The aim of this study was to examine the hypothesis that a combination of proteasome inhibition by bortezomib and immune therapy with interleukin-12 (IL-12) can produce enhanced antitumor efficacy relative to the effects of either of these agents alone. A mouse xenograft model of myeloma was developed. The mice were randomly divided into saline control (NS), IL-12 (0.4 µg/animal; intraperitoneal), bortezomib (0.75 mg/kg; intravenous), and bortezomib+IL-12 groups. Effects of treatments on tumor growth were assessed by before and after treatment comparisons and group comparisons. The effects of various treatments on the number of peripheral blood lymphocytes and natural killer (NK) cells were assessed by complete blood count and flow cytometry analysis. The cell-killing function of NK cells in splenocytes was evaluated using the lactate dehydrogenase release assay. IL-12 treatment alone produced a mild decrease in tumor volume compared with control (P>0.05). Bortezomib alone resulted in substantial inhibition of tumor growth at varying time points, reaching ~65 and ~60% reduction in tumor volume after 15 and 21 days of therapy, respectively. At the same time points, the combination therapy produced ~75 and ~84% decreases in tumor growth, respectively, which were significantly greater than the reduction produced by bortezomib monotherapy. Tumors resumed growth upon termination of bortezomib treatment at 2 weeks, although the tumor volume was still significantly smaller than that in the time-matched NS and IL-12 animals. This rebound of tumor growth was completely prevented with the combination therapy, and tumor volume continued to decrease throughout the time course. The percentage and total number of NK cells were significantly decreased after bortezomib monotherapy and combination therapy; however, they remained unaltered after IL-12 treatment compared with no treatment. Further, combination therapy significantly restored the bortezomib-induced functional impairment of the cell-killing capability of NK cells, relative to bortezomib alone. We conclude that the bortezomib-IL-12 combination therapy offers superior antitumor efficacy over monotherapy with either bortezomib or IL-12 in a mouse model of myeloma. Restoration of bortezomib-induced functional impairment of NK cells by IL-12 may be a mechanism for the synergetic effects of the two agents. Therefore, a combination of the two agents may represent a more rational therapeutic approach for myeloma.
authors.affiliation: Departments of aOncology bHematology, Qilu Hospital, Shandong University cDepartment of Hematology, The Second Hospital of Shandong University, Jinan, People's Republic of China dChildhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska University Hospital eDivision of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xiangling
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Feng
authors.forename: Juandong
authors.initials: J
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Shao
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ji
authors.forename: Daoxin
authors.initials: D
authors.lastname: Ma
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Chengyun
authors.initials: C
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D064593:Heterografts; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009368:Neoplasm Transplantation; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D018664:Interleukin-12; D000069286:Bortezomib