Statins (HMG-CoA reductase inhibitors) are known to show antiproliferative effects and are anticipated as a potential drug in the treatment of malignancies including acute myelogenous leukemia (AML) and multiple myeloma (MM). Using cell proliferation assays, we determined the effects of simvastatin in CML cells. In the current study we show that simvastatin inhibits the proliferation of CML cell lines (The IC50 to simvastatin of K562, Kcl22, and LAMA84 were 13 uM, 19 uM, and 31 uM, respectively). Moreover, synergistic interactions between simvastatin and imatinib were observed in imatinib-resistant CML cell lines (K562-r, KCL22-r, and LAMA84-r). The cytotoxic effect of simvastatin occurred via the induction of apoptosis and inhibited Bcr-Abl tyrosine kinase (TK) activity, as evidenced by annexin V assay and Western blot analyses. Co-treatment with imatinib and simvastatin decreased the amount of Bcr-Abl protein and stimulated the import of Abl protein in the nuclei in K562 cells. Simvastatin may be a potential candidate for the treatment of imatinib-resistant CML patients and the effective dose of imatinib could be reduced in a combined treatment with simvastatin. Mean combination index (CI) values at 50%, 75%, and 90% growth inhibition (IC50, IC80) derived from combined treatment experiments

Cell lineDrug combinationDrug ratioCI: IC50CI: IC75CI: IC90
Gradual levels of synergy are marked as recommended by the manufacture of the Calcusyn software: +++, strong synergism; ++, moderate synergism; + slight synergism; ±, nearly additive; −, slight antagonism: and − −, moderate antagonism 
K562-s Imatinib + Simvastatin 1:40 0.61+++ 0.49+++ 0.40+++ 
K562-r Imatinib + Simvastatin 1:10 0.60+++ 0.46+++ 0.41+++ 
Kcl22-s Imatinib + Simvastatin 1:100 0.96± 1.32− 1.83− − 
Kcl22-r Imatinib + Simvastatin 1:1 0.42+++ 0.35+++ 0.30+++ 
LAMA84-s Imatinib + Simvastatin 1:200 1.20− 1.0± 1.0± 
LAMA84-r Imatinib + Simvastatin 1:20 0.99± 0.8+ 0.84+ 
Cell lineDrug combinationDrug ratioCI: IC50CI: IC75CI: IC90
Gradual levels of synergy are marked as recommended by the manufacture of the Calcusyn software: +++, strong synergism; ++, moderate synergism; + slight synergism; ±, nearly additive; −, slight antagonism: and − −, moderate antagonism 
K562-s Imatinib + Simvastatin 1:40 0.61+++ 0.49+++ 0.40+++ 
K562-r Imatinib + Simvastatin 1:10 0.60+++ 0.46+++ 0.41+++ 
Kcl22-s Imatinib + Simvastatin 1:100 0.96± 1.32− 1.83− − 
Kcl22-r Imatinib + Simvastatin 1:1 0.42+++ 0.35+++ 0.30+++ 
LAMA84-s Imatinib + Simvastatin 1:200 1.20− 1.0± 1.0± 
LAMA84-r Imatinib + Simvastatin 1:20 0.99± 0.8+ 0.84+ 
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Topics:
cell lines, imatinib mesylate, leukemia, myelocytic, chronic, simvastatin, combined modality therapy, statins, annexin a5, bcr-abl tyrosine kinase, cancer, drug combinations

Author notes

Disclosure: No relevant conflicts of interest to declare.

2007, The American Society of Hematology
2007
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