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Simvastatin Induces Death of Multiple Myeloma Cell Lines
  1. Naomi Gronich,
  2. Liat Drucker,
  3. Hava Shapiro,
  4. Judith Radnay,
  5. Shai Yarkoni,
  6. Michael Lishner
  1. From the Department of Medicine (N.G., M.L.), Oncogenetic (N.G., L.D., S.Y., M.L.) and Hematology (H.S., J.R.) Laboratories, Sapir Medical Center, Meir Hospital, Kfar-Saba, Israel; and Sackler Faculty of Medicine (M.L.), Tel Aviv University, Tel Aviv, Israel.
  2. Supported by Tel Aviv University research grant #06-0138-0296-390007. Merck generously provided the simvastatin used in this study.
  3. Address correspondence to: Dr. Liat Drucker, Oncogenetic Laboratory, Sapir Medical Center, Meir Hospital, Kfar Sava 44281, Israel; e-mail: druckerl{at}clalit.org.il.

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 μM) 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 μM for ARH77, 8 μM for RPMI 8226, and 13 μM 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.

Key Words
  • myeloma
  • simvastatin
  • apoptosis
  • interleukin-6
  • calcium

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