TY - JOUR AB - Simvastatin is a low density lipoprotein‑lowering drug that is widely used to prevent and treat cardiovascular disease by inhibiting the mevalonate pathway. Simvastatin also exhibits inhibitory effects on a number of types of cancer. In the present study, the effects of simvastatin on the activity of doxorubicin in the breast cancer MCF‑7 cell line, and the mechanisms by which this interaction occurs were investigated. The effect of simvastatin and doxorubicin treatment, alone and in combination, on the growth of MCF‑7 cells was evaluated by a sulforhodamine B and colony formation assay. To delineate the mechanisms of cell death, the following parameters were measured: Reactive oxygen species (ROS) production using the fluorescence probe dihydroethidium; caspase 3 activity by the fluorometry method; gene expression by quantitative polymerase chain reaction; and apoptotic‑ and proliferative‑related protein levels by western blotting. MCF‑7 cell proliferation was significantly suppressed by 24‑48 h treatment with simvastatin alone. Doses of 10‑50 µM simvastatin also enhanced the cytotoxicity of doxorubicin against MCF‑7 cells in a dose‑dependent manner, and decreased the colony‑forming ability of MCF‑7 cells. Simvastatin alone or in combination with doxorubicin significantly increased ROS levels. Combination treatment significantly decreased expression of the cell cycle regulatory protein Ras‑related C3 botulinum toxin substrate 1 and numerous downstream proteins including cyclin‑dependent kinase (Cdk) 2, Cdk4 and Cdk6. Additionally, simvastatin in combination with doxorubicin significantly induced expression of the cyclin‑dependent kinase inhibitor p21, increased cytochrome c and caspase 3 expression and reduced cyclin D1 expression. In conclusion, simvastatin acts synergistically with the anticancer drug doxorubicin against MCF‑7 cells, possibly through a downregulation of the cell cycle or induction of apoptosis. Although additional studies are required, simvastatin and doxorubicin combination may be a reasonable regimen for the treatment of breast cancer. AD - Faculty of Medicine, Mahasarakham University, Talad, Maha Sarakham 44000, Thailand College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani, Warin chamrap, Ubon Ratchathani 34190, Thailand Division of Pharmacology, Department of Preclinical Science, Faculty of Medicine, Thammasat University, Rangsit, Pathum Thani 12120, Thailand AU - Buranrat,Benjaporn AU - Suwannaloet,Wanwisa AU - Naowaboot,Jarinyaporn DA - 2017/11/01 DO - 10.3892/ol.2017.6783 EP - 6250 IS - 5 JO - Oncol Lett KW - simvastatin doxorubicin breast cancer Ras‑related C3 botulinum toxin substrate 1 caspase 3 PY - 2017 SN - 1792-1074 1792-1082 SP - 6243 ST - Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells T2 - Oncology Letters TI - Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells UR - https://doi.org/10.3892/ol.2017.6783 VL - 14 ER -