Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
July-2015 Volume 12 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
July-2015 Volume 12 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

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

  • Authors:
    • Yuanyuan Shen
    • Yingying Du
    • Ying Zhang
    • Yueyin Pan
  • View Affiliations / Copyright

    Affiliations: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, Department of Geriatrics, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P.R. China
  • Pages: 456-462
    |
    Published online on: March 3, 2015
       https://doi.org/10.3892/mmr.2015.3406
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Breast cancer is associated with high levels of incidence, morbidity and mortality; therefore, the identification of effective chemopreventive strategies is crucial. It is important for clinicians to be able to identify the populations at risk who would benefit from chemoprevention, and the interventions that are effective and safe. The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF‑7 human breast cancer cells. The anti‑proliferative effects of simvastatin and exemestane, alone and in combination, on the growth of MCF‑7 human breast cancer cells were assessed by MTT assay. The synergism between the two drugs was determined in vitro using the combination index (CI) analysis. Cell cycle distribution and apoptosis were analyzed by flow cytometry, and alterations to the signaling pathway in MCF‑7 cells were examined by immunoblotting following treatment with various regimens. The results of the MTT assay indicated that the combined treatment of simvastatin and exemestane significantly decreased the viability of MCF‑7 estrogen receptor‑positive (ER+) human breast cancer cells, as compared with those that were treated with the individual drugs (CI<1). In addition, coadministration of exemestane and simvastatin was shown to result in marked inhibition of tumor cell proliferation, significant cell cycle arrest at G0/G1 phase and induction of apoptosis, as compared with that of the control and individual drug‑treated cells. Furthermore, the results of the present study indicated that these synergistic effects may be associated with the B‑cell lymphoma 2 (Bcl‑2)/Bcl‑2‑associated X protein apoptotic pathway and the mitogen‑activated protein kinase/mammalian target of rapamycin/p70S6 kinase growth pathway. The combination of exemestane and simvastatin generated synergistic effects on MCF‑7 ER+ breast cancer cells, indicating that the combination of these drugs may be a potential therapeutic strategy for the treatment of hormone‑dependent breast cancer. The combination of the two inhibitors markedly increased the efficacy, as compared with the single‑agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer. The results of the present study suggested that this combination of drugs has therapeutic potential, and requires further mechanistic and biomarker investigations in clinical trials.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Ferlay J, Parkin DM and Steliarova-Foucher E: Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 46:765–781. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Chen S: An “omics” approach to determine the mechanisms of acquired aromatase inhibitor resistance. OMICS. 15:347–352. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Jankowitz RC and Davidson NE: Adjuvant endocrine therapy for breast cancer: how long is long enough? Oncology (Williston Park). 27:1210–1216. 2013.

4 

Campagnoli C, Pasanisi P, Castellano I, Abba C, Brucato T and Berrino F: Postmenopausal breast cancer, androgens, and aromatase inhibitors. Breast Cancer Res Treat. 139:1–11. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Riemsma R, Forbes CA, Kessels A, et al: Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer. Breast Cancer Res Treat. 123:9–24. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Li Z, Gu X, Tong J, et al: A meta-analysis of internal mammary lymph node metastasis in breast cancer patients. Onkologie. 36:747–752. 2013.PubMed/NCBI

7 

Morris PG, McArthur HL and Hudis CA: Therapeutic options for metastatic breast cancer. Expert Opin Pharmacother. 10:967–981. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Rizzoli R, Body JJ, De Censi A, Reginster JY, Piscitelli P and Brandi ML; European Society for Clinical and Economical aspects of Osteoporosis and Osteoarthritis (ESCEO): Guidance for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper. Osteoporos Int. 23:2567–2576. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Brodie A and Sabnis G: Adaptive changes result in activation of alternate signaling pathways and acquisition of resistance to aromatase inhibitors. Clin Cancer Res. 17:4208–4213. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Wong WW, Dimitroulakos J, Minden MD and Penn LZ: HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 16:508–519. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Superko HR, Momary KM and Li Y: Statins personalized. Med Clin North Am. 96:123–139. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Goldstein JL and Brown MS: Regulation of the mevalonate pathway. Nature. 343:425–430. 1990. View Article : Google Scholar : PubMed/NCBI

13 

Liao JK: Isoprenoids as mediators of the biological effects of statins. J Clin Invest. 110:285–288. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Wejde J, Blegen H and Larsson O: Requirement for mevalonate in the control of proliferation of human breast cancer cells. Anticancer Res. 12:317–324. 1992.PubMed/NCBI

15 

Spampanato C, De Maria S, Sarnataro M, et al: Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. Int J Oncol. 40:935–941. 2012.

16 

Kochuparambil ST, Al-Husein B, Goc A, Soliman S and Somanath PR: Anticancer efficacy of simvastatin on prostate cancer cells and tumor xenografts is associated with inhibition of Akt and reduced prostate-specific antigen expression. J Pharmacol Exp Ther. 336:496–505. 2011. View Article : Google Scholar

17 

Campbell MJ, Esserman LJ, Zhou Y, et al: Breast cancer growth prevention by statins. Cancer Res. 66:8707–8714. 2006. View Article : Google Scholar : PubMed/NCBI

18 

Cho SJ, Kim JS, Kim JM, Lee JY, Jung HC and Song IS: Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer. 123:951–957. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Nielsen SF, Nordestgaard BG and Bojesen SE: Statin use and reduced cancer-related mortality. N Engl J Med. 367:1792–1802. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Guterres FA, Martinez GR, Rocha ME and Winnischofer SM: Simvastatin rises reactive oxygen species levels and induces senescence in human melanoma cells by activation of p53/p21 pathway. Exp Cell Res. 319:2977–2988. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Cheng WH, Ho WY, Chang CF, et al: Simvastatin induces a central hypotensive effect via Ras-mediated signalling to cause eNOS up-regulation. Br J Pharmacol. 170:847–858. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Ahern TP, Pedersen L, Tarp M, et al: Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst. 103:1461–1468. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Hu LX, Du YY, Zhang Y and Pan YY: Synergistic effects of exemestane and aspirin on MCF-7 human breast cancer cells. Asian Pac J Cancer Prev. 13:5903–5908. 2012. View Article : Google Scholar

24 

Budman DR, Calabro A, Wang LG, et al: Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Cancer Invest. 18:695–701. 2000. View Article : Google Scholar : PubMed/NCBI

25 

Budman DR and Calabro A: In vitro search for synergy and antagonism: evaluation of docetaxel combinations in breast cancer cell lines. Breast Cancer Res Treat. 74:41–46. 2002. View Article : Google Scholar : PubMed/NCBI

26 

Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI

27 

Paridaens RJ, Dirix LY, Beex LV, et al: Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 26:4883–4890. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Sestak I, Cuzick J, Sapunar F, et al ATAC Trialists’ Group: Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol. 9:866–872. 2008. View Article : Google Scholar : PubMed/NCBI

29 

Chen SH, Chou FF and Ko JY: The use of simvastatin with aromasin in an ovariectomized rat model: effects on the skeletal system. Chang Gung Med J. 33:509–514. 2010.PubMed/NCBI

30 

Stoehr M, Mozet C, Boehm A, Aigner A, Dietz A and Wichmann G: Simvastatin suppresses head and neck squamous cell carcinoma ex vivo and enhances the cytostatic effects of chemotherapeutics. Cancer Chemother Pharmacol. 73:827–837. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Danilo C and Frank PG: Cholesterol and breast cancer development. Curr Opin Pharmacol. 12:677–682. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Llaverias G, Danilo C, Mercier I, et al: Role of cholesterol in the development and progression of breast cancer. Am J Pathol. 178:402–412. 2011. View Article : Google Scholar : PubMed/NCBI

33 

Nelson ER, Wardell SE, Jasper JS, et al: 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 342:1094–1098. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Imamura K, Ogura T, Kishimoto A, Kaminishi M and Esumi H: Cell cycle regulation via p53 phosphory-lation by a 5′-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem Biophys Res Commun. 287:562–567. 2001. View Article : Google Scholar : PubMed/NCBI

35 

Jones RG, Plas DR, Kubek S, et al: AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 18:283–293. 2005. View Article : Google Scholar : PubMed/NCBI

36 

Hadad SM, Baker L, Quinlan PR, et al: Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer. 9:3072009. View Article : Google Scholar : PubMed/NCBI

37 

Bühler S and Laufer SA: p38 MAPK inhibitors: a patent review (2012 – 2013). Expert Opin Ther Pat. 24:535–554. 2014. View Article : Google Scholar

38 

Misirkic M, Janjetovic K, Vucicevic L, et al: Inhibition of AMPK-dependent autophagy enhances in vitro antiglioma effect of simvastatin. Pharmacol Res. 65:111–119. 2012. View Article : Google Scholar

39 

Yang PM, Liu YL, Lin YC, Shun CT, Wu MS and Chen CC: Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res. 70:7699–7709. 2010. View Article : Google Scholar : PubMed/NCBI

40 

Woodard J, Sassano A, Hay N and Platanias LC: Statin-dependent suppression of the Akt/mammalian target of rapamycin signaling cascade and programmed cell death 4 up-regulation in renal cell carcinoma. Clin Cancer Res. 14:4640–4649. 2008. View Article : Google Scholar : PubMed/NCBI

41 

Jaafar H, Abdullah S, Murtey MD and Idris FM: Expression of Bax and Bcl-2 in tumour cells and blood vessels of breast cancer and their association with angiogenesis and hormonal receptors. Asian Pac J Cancer Prev. 13:3857–3862. 2012. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Shen Y, Du Y, Zhang Y and Pan Y: Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells. Mol Med Rep 12: 456-462, 2015.
APA
Shen, Y., Du, Y., Zhang, Y., & Pan, Y. (2015). Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells. Molecular Medicine Reports, 12, 456-462. https://doi.org/10.3892/mmr.2015.3406
MLA
Shen, Y., Du, Y., Zhang, Y., Pan, Y."Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells". Molecular Medicine Reports 12.1 (2015): 456-462.
Chicago
Shen, Y., Du, Y., Zhang, Y., Pan, Y."Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells". Molecular Medicine Reports 12, no. 1 (2015): 456-462. https://doi.org/10.3892/mmr.2015.3406
Copy and paste a formatted citation
x
Spandidos Publications style
Shen Y, Du Y, Zhang Y and Pan Y: Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells. Mol Med Rep 12: 456-462, 2015.
APA
Shen, Y., Du, Y., Zhang, Y., & Pan, Y. (2015). Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells. Molecular Medicine Reports, 12, 456-462. https://doi.org/10.3892/mmr.2015.3406
MLA
Shen, Y., Du, Y., Zhang, Y., Pan, Y."Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells". Molecular Medicine Reports 12.1 (2015): 456-462.
Chicago
Shen, Y., Du, Y., Zhang, Y., Pan, Y."Synergistic effects of combined treatment with simvastatin and exemestane on MCF‑7 human breast cancer cells". Molecular Medicine Reports 12, no. 1 (2015): 456-462. https://doi.org/10.3892/mmr.2015.3406
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team