Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells

Shen, Yuanyuan; Du, Yingying; Zhang, Ying; Pan, Yueyin

doi:10.3892/mmr.2015.3406

Cited by 20 publications

(10 citation statements)

References 39 publications

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“…In the present study, simvastatin significantly inhibited breast cancer cell proliferation with IC 50 values in the low micromolar range. This result is concomitant with the data of previous studies (16,18). Simvastatin stimulates cell cycle arrest and apoptosis in a number of cancer cell types (32) via the intracellular signaling mechanisms of RAC1 and the associated downstream pathway.…”

Section: Discussionsupporting

confidence: 80%

“…In addition, statins perform roles in immune regulation (11), the inhibition of inflammation (12) and the modulation of angiogenesis (13). Statins also exhibit anticancer activities (14,15), decrease cellular proliferation (15)(16)(17) and induce apoptosis (15,18,19) in breast, colorectal, lung, prostate and pancreatic cancer (20). Notably, statins inhibit cancer cell growth in vivo and decrease metastasis at clinically therapeutic doses (21).…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells

2017

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Abstract. 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.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells

2017

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“…Also in vivo study displayed that the administration of the combination of TAM and SIM resulted in an insignificant decrease in the tumor volume compared to TAM treated mice. On the other hand, and contrary to our results, the combination of exemestane (an aromatase inhibitor) and simvastatin generated synergistic effects on MCF-7 ER+ breast cancer cells 58. Also, SIM in combination with doxorubicin suppress the prosurvival ERK1/2 pathway in a Ca 2+ independent and Ca 2+ dependent manner 59,60.…”

Section: Discussioncontrasting

confidence: 98%

“…The controversy between the results of our study and the previous ones may be due to either differences in the drug in combination with TAM or in the cell line type. In the first two studies, the authors used exemestane,58 an aromatase inhibitor, or doxorubicin59 that are of different classes and mechanisms from TAM. In the study of Liang et al,61 the cell line was TAM resistant MCF-7, which is biologically and metabolically different from the TAM-sensitive one.…”

Section: Discussionmentioning

confidence: 99%

<p>Simvastatin Evokes An Unpredicted Antagonism For Tamoxifen In MCF-7 Breast Cancer Cells</p>

Ibrahim¹,

Zaki²,

Wadie³

et al. 2019

CMAR

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PurposeTamoxifen (TAM) is a non-steroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM) is a lipid-lowering agent and has been shown to inhibit cancer cell growth. The study aimed to investigate the effect of the combination of TAM and SIM in the treatment of estrogen receptor positive (ER+) breast cancer cell line, MCF-7, and in mice-bearing Ehrlich solid tumors.MethodsMCF-7 cells were treated with different concentrations of TAM or/and SIM for 72 hours and the effects of the combination treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated using different techniques. In addition, tumor volume, oxidative markers, and inflammatory markers of the combined therapy were explored in mice bearing solid EAC tumors.ResultsThe results showed that treatment of MCF-7 cells with the combination of 10 µM TAM, and 2 µM SIM significantly inhibited the increase in oxidative stress markers, LDH, and NF-kB induced by TAM. In addition, there was a significant decrease in the total apoptotic ratio, caspase-3 activity, and glucose uptake, while there was a non-significant change in Bax/bcl-2 ratio compared to the TAM-treated group. Using the isobologram equation, the drug interaction was antagonistic with combination index, CI=1.18. On the other hand, the combination regimen decreased VEGF, and matrix metalloproteinases, MMP 2&9 compared to TAM-treated cells. Additionally, in vivo, the combination regimen resulted in a non-significant decrease in the tumor volume, decreased oxidative markers, and the protein expression of TNF-α, and NF-κB compared to the TAM treated group.ConclusionAlthough the combination regimen of TAM and SIM showed an antagonistic drug interaction in MCF-7 breast cancer, it displayed favorable antiangiogenic, anti-metastatic, and anti-inflammatory effects.

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“…Simvastatin also induces pro-apoptotic Bcl2 family members Bcl2 and Bax in MCF-7 and MDA-MB231 cells in a time- and dose-dependent manner3839. These effects were also caspase-dependent since simvastatin increased caspase-3 and -9 activity in MDA-MB231 cells39.…”

Section: Discussionmentioning

confidence: 97%

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

Alizadeh

Zeki²,

Mirzaei

et al. 2017

Sci Rep

119

112

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The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.

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Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells

Cited by 20 publications

References 39 publications

Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells

Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells

<p>Simvastatin Evokes An Unpredicted Antagonism For Tamoxifen In MCF-7 Breast Cancer Cells</p>

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

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