title: Simvastatin induces death of multiple myeloma cell lines.
abstract: BACKGROUND
  Accumulating reports indicate that statins widely prescribed for hypercholesteromia have antineoplastic activity. We hypothesized that because statins inhibit farnesylation of Ras that is often mutated in multiple myeloma (MM), as well as the production of interleukin (IL)-6, a key cytokine in MM, they may have antiproliferative and/or proapoptotic effects in this malignancy.
  
  
  METHODS
  U266, RPMI 8226, and ARH77 were treated with simvastatin (0-30 microM) for 5 days. The following aspects were evaluated: viability (IC50), cell cycle, cell death, cytoplasmic calcium ion levels, supernatant IL-6 levels, and tyrosine kinase activity.
  
  
  RESULTS
  Exposure of all cell lines to simvastatin resulted in reduced viability with IC50s of 4.5 microM for ARH77, 8 microM for RPMI 8226, and 13 microM for U266. The decreased viability is attributed to cell-cycle arrest (U266, G1; RPMI 8226, G2M) and cell death. ARH77 underwent apoptosis, whereas U266 and RPMI 8226 displayed a more necrotic form of death. Cytoplasmic calcium levels decreased significantly in all treated cell lines. IL-6 secretion from U266 cells was abrogated on treatment with simvastatin, whereas total tyrosine phosphorylation was unaffected.
  
  
  CONCLUSIONS
  Simvastatin displays significant antimyeloma activity in vitro. Further research is warranted for elucidation of the modulated molecular pathways and clinical relevance.
authors.affiliation: Department of Medicine, Laboratories, Sapir Medical Center, Meir Hospital, Kfar-Saba, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Gronich
authors.forename: Liat
authors.initials: L
authors.lastname: Drucker
authors.forename: Hava
authors.initials: H
authors.lastname: Shapiro
authors.forename: Judith
authors.initials: J
authors.lastname: Radnay
authors.forename: Shai
authors.initials: S
authors.lastname: Yarkoni
authors.forename: Michael
authors.initials: M
authors.lastname: Lishner
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D010766:Phosphorylation; D019821:Simvastatin / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D015850:Interleukin-6; D014443:Tyrosine; D019821:Simvastatin; D002118:Calcium