Browse > Article
http://dx.doi.org/10.7314/APJCP.2012.13.11.5903

Synergistic Effects of Exemestane and Aspirin on MCF-7 Human Breast Cancer Cells  

Hu, Li-Xia (Department of Oncology, The First Affiliated Hospital of Anhui Medical University)
Du, Ying-Ying (Department of Oncology, The First Affiliated Hospital of Anhui Medical University)
Zhang, Ying (Department of Geriatrics, The Third Affiliated Hospital of Anhui Medical University)
Pan, Yue-Yin (Department of Oncology, The First Affiliated Hospital of Anhui Medical University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.13, no.11, 2012 , pp. 5903-5908 More about this Journal
Abstract
Objective: The purpose of this study is to investigate the combined effects of exemestane and aspirin on MCF-7 human breast cancer cells. Methods: Antiproliferative effects of exemestane and aspirin, alone and in combination, on growth of MCF-7 human breast cancer cells were assessed using the MTT assay. Synergistic interaction between the two drugs was evaluated in vitro using the combination index (CI) method. The cell cycle distribution was analyzed by flow cytometry and Western blotting was used to investigate the expression of cyclooxygenase-1, cyclooxygenase-2 and Bcl-2. Results: MTT assays indicated that combination treatment obviously decreased the viability of MCF-7 human breast cancer cells compared to individual drug treatment (CI<1). In addition, the combination of exemestane and aspirin exhibited a synergistic inhibition of cell proliferation, significantly arrested the cell cycle in the $G_0/G_1$ phase and produced a stronger inhibitory effect on COX-1 and Bcl-2 expression than control or individual drug treatment. Conclusion: These results indicate that the combination of exemestane and aspirin might become a useful method to the treatment of hormone-dependent breast cancer. The combination of the two inhibitors significantly increased the response as compared to single agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer.
Keywords
Exemestane; aspirin; MCF-7; combination treatment; synergistic effect;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Abbadessa G, Spaccamiglio A, Sartori ML, et al (2006). The aspirin metabolite, salicylate, inhibits 7,12-dimethylbenz[a] anthracene-DNA adduct formation in breast cancer cells. Int J Oncol, 28, 1131-40.
2 Basu GD, Liang WS, Stephan DA, et al (2006). A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. Breast Cancer Res, 8, R69.   DOI
3 Chan AT, Ogino S, Fuchs CS (2007). Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med, 356, 2131-42.   DOI
4 Chou TC, Talalay P (1984). Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul, 22, 27-55.   DOI   ScienceOn
5 Chulada PC, Thompson MB, Mahler JF, et al (2000). Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res, 60, 4705-8.
6 Connolly EM, Harmey JH, O'Grady T, et al (2002). Cyclooxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer. Br J Cancer, 87, 231-7.   DOI   ScienceOn
7 Daikoku T, Tranguch S, Chakrabarty A, et al (2007). Extracellular signal-regulated kinase is a target of cyclooxygenase-1-peroxisome proliferator-activated receptor-delta signaling in epithelial ovarian cancer. Cancer Res, 67, 5285-92.   DOI
8 Daikoku T, Tranguch S, Trofimova IN, et al (2006). Cyclooxygenase-1 is overexpressed in multiple genetically engineered mouse models of epithelial ovarian cancer. Cancer Res, 66, 2527-31.   DOI
9 Daikoku T, Wang D, Tranguch S, et al (2005). Cyclooxygenase-1 is a potential target for prevention and treatment of ovarian epithelial cancer. Cancer Res, 65, 3735-44.   DOI
10 Davies G, Martin LA, Sacks N, et al (2002). Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention. Ann Oncol, 13, 669-78.   DOI
11 Diaz-Cruz ES, Shapiro CL, Brueggemeier RW (2005). Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells. J Clin Endocrinol Metab, 90, 2563-70.   DOI   ScienceOn
12 Gately S (2000). The contributions of cyclooxygenase-2 to tumor angiogenesis. Cancer Metastasis Rev, 19, 19-27.   DOI   ScienceOn
13 Diel P, Smolnikar K, Michna H (1999). The pure antiestrogen ICI 182780 is more effective in the induction of apoptosis and down regulation of BCL-2 than tamoxifen in MCF-7 cells. Breast Cancer Res Treat, 58, 87-97.   DOI
14 Dong Z, Huang C, Brown RE, et al (1997). Inhibition of activator protein 1 activity and neoplastic transformation by aspirin. J Biol Chem, 272, 9962-70.   DOI   ScienceOn
15 Erovic BM, Woegerbauer M, Pammer J, et al (2008). Strong evidence for up-regulation of cyclooxygenase-1 in head and neck cancer. Eur J Clin Invest, 38, 61-6.
16 Geisler J, Lonning PE (2005). Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res, 11, 2809-21.   DOI
17 Ghosh N, Chaki R, Mandal V, et al (2010). COX-2 as a target for cancer chemotherapy. Pharmacol Rep, 62, 233-44.   DOI
18 Goldhirsch A, Glick JH, Gelber RD, et al (2005). Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol, 16, 1569-83.   DOI   ScienceOn
19 Gupta RA, Tejada LV, Tong BJ, et al (2003). Cyclooxygenase-1 is overexpressed and promotes angiogenic growth factor production in ovarian cancer. Cancer Res, 63, 906-11.
20 Harris RE, Robertson FM, Abou-Issa HM, et al (1999). Genetic induction and upregulation of cyclooxygenase (COX) and aromatase (CYP19): an extension of the dietary fat hypothesis of breast cancer. Med Hypotheses, 52, 291-2.   DOI   ScienceOn
21 Hwang D, Scollard D, Byrne J, et al (1998). Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst, 90, 455-60.   DOI   ScienceOn
22 Hiraga T, Myoui A, Choi ME, et al (2006). Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-beta enhances bone metastases in breast cancer. Cancer Res, 66, 2067-73.   DOI
23 Howe LR (2007). Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. Breast Cancer Res, 9, 210.   DOI
24 Howe LR, Lippman SM (2008). Modulation of breast cancer risk by nonsteroidal anti-inflammatory drugs. J Natl Cancer Inst, 100, 1420-3.   DOI
25 Janicke F (2007). Continuing with letrozole offers greater benefits. J Cancer Res Clin Oncol, 133, 445-53.   DOI
26 Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.   DOI
27 Juuti A, Louhimo J, Nordling S, et al (2006). Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer. J Clin Pathol, 59, 382-6.   DOI
28 Kanthamneni N, Chaudhary A, Wang J, et al (2010). Nanoparticulate delivery of novel drug combination regimens for the chemoprevention of colon cancer. Int J Oncol, 37, 177-85.
29 Kirschenbaum A, Klausner AP, Lee R, et al (2000). Expression of cyclooxygenase-1 and cyclooxygenase-2 in the human prostate. Urology, 56, 671-6.   DOI
30 Kundu N, Fulton AM (2002). Selective cyclooxygenase (COX)-1 or COX-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res, 62, 2343-6.
31 Masferrer JL, Leahy KM, Koki AT, et al (2000). Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res, 60, 1306-11.
32 Leahy KM, Ornberg RL, Wang Y, et al (2002). Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res, 62, 625-31.
33 Liu XH, Rose DP (1996). Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res, 56, 5125-7.
34 Lu M, Strohecker A, Chen F, et al (2008). Aspirin sensitizes cancer cells to TRAIL-induced apoptosis by reducing survivin levels. Clin Cancer Res, 14, 3168-76.   DOI   ScienceOn
35 McFadden DW, Riggs DR, Jackson BJ, et al (2006). Additive effects of Cox-1 and Cox-2 inhibition on breast cancer in vitro. Int J Oncol, 29, 1019-23.
36 Mohseni H, Zaslau S, McFadden D, et al (2004). COX-2 inhibition demonstrates potent anti-proliferative effects on bladder cancer in vitro. J Surg Res, 119, 138-42.   DOI
37 Pillinger MH, Capodici C, Rosenthal P, et al (1998). Modes of action of aspirin-like drugs: salicylates inhibit erk activation and integrin-dependent neutrophil adhesion. Proc Natl Acad Sci U S A, 95, 14540-5.   DOI
38 Riemsma R, Forbes CA, Kessels A, et al (2010). 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.   DOI
39 Ristimaki A, Sivula A, Lundin J, et al (2002). Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res, 62, 632-5.
40 Ruvolo PP, Deng X, May WS (2001). Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia, 15, 515-22.
41 Smith IE, Dowsett M (2003). Aromatase inhibitors in breast cancer. N Engl J Med, 348, 2431-42.   DOI
42 Sales KJ, Katz AA, Howard B, et al (2002). Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1. Cancer Res, 62, 424-32.
43 Sheng H, Shao J, Morrow JD, et al (1998). Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res, 58, 362-6.
44 Slattery ML, Curtin K, Baumgartner R, et al (2007). IL6, aspirin, nonsteroidal anti-inflammatory drugs, and breast cancer risk in women living in the southwestern United States. Cancer Epidemiol Biomarkers Prev, 16, 747-55.   DOI
45 Son DS, Wilson AJ, Parl AK, et al (2010). The effects of the histone deacetylase inhibitor romidepsin (FK228) are enhanced by aspirin (ASA) in COX-1 positive ovarian cancer cells through augmentation of p21. Cancer Biol Ther, 9, 928-35.   DOI
46 Surowiak P, Materna V, Matkowski R, et al (2005). Relationship between the expression of cyclooxygenase 2 and MDR1/Pglycoprotein in invasive breast cancers and their prognostic significance. Breast Cancer Res, 7, R862-70.   DOI
47 Taketo MM (1998). Cyclooxygenase-2 inhibitors in tumorigenesis (Part II). J Natl Cancer Inst, 90, 1609-20.   DOI
48 Timoshenko AV, Xu G, Chakrabarti S, et al (2003). Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells. Exp Cell Res, 289, 265-74.   DOI
49 Tsatsanis C, Androulidaki A, Venihaki M, et al (2006). Signalling networks regulating cyclooxygenase-2. Int J Biochem Cell Biol, 38, 1654-61.   DOI   ScienceOn
50 Van Dyke AL, Cote ML, Prysak G, et al (2008). Regular adult aspirin use decreases the risk of non-small cell lung cancer among women. Cancer Epidemiol Biomarkers Prev, 17, 148-57.   DOI
51 Winer EP, Hudis C, Burstein HJ, et al (2005). American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol, 23, 619-29.   DOI
52 Xu XM, Sansores-Garcia L, Chen XM, et al (1999). Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci U S A, 96, 5292-7.   DOI   ScienceOn