title: Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate.
abstract: OBJECTIVE
  The use of new drugs has improved the treatment of multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Nevertheless, over time many patients relapse and develop resistance to treatment, and efforts are needed to overcome drug resistance. The widely used malaria drug artesunate has been reported to have antitumor activity, and we aimed to test the effects of artesunate on a panel of myeloma and lymphoma cells.
  
  
  METHODS
  Myeloma and DLBCL cell lines were treated with artesunate in vitro. The effects of artesunate treatment were evaluated using ATP content measurements for proliferation and annexin V/propidium iodide labeling for apoptosis. Western blotting was used to look for artesunate-induced protein changes. In addition, we measured artesunate effects on patient myeloma cells in the presence of bone marrow stromal cells.
  
  
  RESULTS
  Artesunate treatment efficiently inhibited cell growth and induced apoptosis in cell lines. Apoptosis was induced concomitantly with downregulation of MYC and anti-apoptotic Bcl-2 family proteins, as well as with cleavage of caspase-3. The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 μm. Furthermore, some primary myeloma cells were also sensitive to artesunate at doses around 10 μm. Concentrations of this order are pharmacologically relevant as they can be obtained in plasma after intravenous administration of artesunate for malaria treatment.
  
  
  CONCLUSIONS
  Our findings indicate that artesunate is a potential drug for treatment of multiple myeloma and DLBCL at doses of the same order as currently in use for treatment of malaria without serious adverse effects.
authors.affiliation: Department of Cancer Research and Molecular Medicine, KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Toril
authors.initials: T
authors.lastname: Holien
authors.forename: Oddrun E
authors.initials: OE
authors.lastname: Olsen
authors.forename: Kristine
authors.initials: K
authors.lastname: Misund
authors.forename: Hanne
authors.initials: H
authors.lastname: Hella
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
authors.forename: Torstein B
authors.initials: TB
authors.lastname: Rø
authors.forename: Anders
authors.initials: A
authors.lastname: Sundan
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D058492:Drug Repositioning; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D000077332:Artesunate; D000255:Adenosine Triphosphate; D053148:Caspase 3
keywords: apoptosis; artesunate; diffuse large B-cell lymphoma; multiple myeloma; therapy