Download PDF
Drug Res (Stuttg) 2021; 71(06): 307-311
DOI: 10.1055/a-1345-7890
Original Article

Growth Promotion and Increased ATP-Binding Cassette Transporters Expression by Liraglutide in Triple Negative Breast Cancer Cell Line MDA-MB-231

Amir Shadboorestan
1   Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
,
Parastoo Tarighi
2   Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Mahsa Koosha
3   Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
,
Homa Faghihi
4   Department of Pharmaceutics, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
,
Mohammad Hossein Ghahremani
5   Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Hamed Montazeri
3   Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
› Author Affiliations Funding This investigation was supported by deputy of research, Iran University of Medical Sciences, grant No. 960220631570.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Background Glucagon-like petide-1 (GLP-1) agonists such as liraglutide are widely employed in type 2 diabetes due to their glucose reducing properties and small risk of hypoglycemia. Recently, it has been shown that GLP-1agonists can inhibit breast cancer cells growth. Nonetheless, concerns are remained about liraglutide tumor promoting effects as stated by population studies.

Material and Methods We evaluated the effects liraglutide on proliferation of MDA-MB-231 cells by MTT assay and then ATP-binding cassette (ABC) transporters expressions assessed by Real time PCR. Statistical comparisons were made using one-way analysis of variance followed by a post hoc Dunnett test.

Results Here, we report that liraglutide can stimulate the growth of highly invasive triple negative cell line MDA-MB-231; which can be attributed to AMPK-dependent epithelial-mesenchymal transition (EMT) happening in MDA-MB-231 context. Toxicity effects were only observed with concentrations far above the serum liraglutide concentration. ATP-binding cassette (ABC) transporters expressions were upregulated, indicating the possible drug resistance and increased EMT.

Conclusion In conclusion, these results suggest that liraglutide should be used with caution in patients who are suffering or have the personal history of triple negative breast cancer. However, more detailed studies are required to deepen understanding of liraglutide consequences in triple negative breast cancer. ▶Graphical Abstract.

Zoom Image

Key words

liraglutide - Triple negative breast cancer (TNBC) - ATP- binding cassette (ABC) transporters - Glucagon-like petide-1 (GLP-1)


Publication History

Received: 26 November 2020

Accepted: 29 December 2020

Article published online:
21 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Noto H, Tsujimoto T, Sasazuki T. et al. Significantly increased risk of cancer in patients with diabetes mellitus: A systematic review and meta-analysis. Endocr Pract 2011; 17: 616-628
    CrossrefPubMedGoogle Scholar
  • 2 Tsilidis KK, Kasimis JC, Lopez DS. et al. Type 2 diabetes and cancer: Umbrella review of meta-analyses of observational studies. BMJ 2015; 350: g7607
    CrossrefPubMedGoogle Scholar
  • 3 Lipscombe LL, Fischer HD, Austin PC. et al. The association between diabetes and breast cancer stage at diagnosis: A population-based study. Breast Cancer Res Treat 2015; 150: 613-620
    CrossrefPubMedGoogle Scholar
  • 4 Calle EE, Rodriguez C, Walker-Thurmond K. et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625-1638
    CrossrefPubMedGoogle Scholar
  • 5 Davis AA, Kaklamani VG. Metabolic syndrome and triple-negative breast cancer: A new paradigm. Int J Breast Cancer 2012; 2012 809291
    PubMedGoogle Scholar
  • 6 Nauck MA. Unraveling the science of incretin biology. Eur J Intern Med 2009; 20 Suppl 2 S303-S308
    CrossrefPubMedGoogle Scholar
  • 7 Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-2157
    CrossrefPubMedGoogle Scholar
  • 8 Donnelly D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol 2012; 166: 27-41
    CrossrefPubMedGoogle Scholar
  • 9 Deacon CF, Nauck MA, Toft-Nielsen M. et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44: 1126-1131
    CrossrefPubMedGoogle Scholar
  • 10 Neumiller JJ, Campbell RK. Liraglutide: a once-daily incretin mimetic for the treatment of type 2 diabetes mellitus. Ann Pharmacother 2009; 43: 1433-1444
    CrossrefPubMedGoogle Scholar
  • 11 Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004; 145: 2653-2659
    CrossrefPubMedGoogle Scholar
  • 12 Ligumsky H, Wolf I, Israeli S. et al. The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat 2012; 132: 449-461
    CrossrefPubMedGoogle Scholar
  • 13 Fidan-Yaylali G, Dodurga Y, Secme M. et al. Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells. Tumour Biol 2016; 37: 2647-2653
    CrossrefPubMedGoogle Scholar
  • 14 Hicks BM, Yin H, Yu OH. et al. Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink. BMJ 2016; 355: i5340
    PubMedGoogle Scholar
  • 15 Bolen SD, Maruthur NM. Glucagon-like peptide-1 receptor agonists and risk of breast cancer. BMJ 2016; 355: i5519
    CrossrefPubMedGoogle Scholar
  • 16 Zhao W, Zhang X, Zhou Z. et al. Liraglutide inhibits the proliferation and promotes the apoptosis of MCF-7 human breast cancer cells through downregulation of microRNA-27a expression. Mol Med Rep 2018; 17: 5202-5212
    PubMedGoogle Scholar
  • 17 Comsa S, Cimpean AM, Raica M. The story of MCF-7 breast cancer cell line: 40 years of experience in research. Anticancer Res 2015; 35: 3147-3154
    PubMedGoogle Scholar
  • 18 Korner M, Stockli M, Waser B. et al. GLP-1 receptor expression in human tumors and human normal tissues: Potential for in vivo targeting. J Nucl Med 2007; 48: 736-743
    CrossrefPubMedGoogle Scholar
  • 19 Krasner NM, Ido Y, Ruderman NB. et al. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One 2014; 9: e97554
    CrossrefPubMedGoogle Scholar
  • 20 Andreozzi F, Raciti GA, Nigro C. et al. The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. J Transl Med 2016; 14: 229
    CrossrefPubMedGoogle Scholar
  • 21 Faubert B, Vincent EE, Poffenberger MC. et al. The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Lett 2015; 356 (2 Pt A): 165-170
    CrossrefPubMedGoogle Scholar
  • 22 Saxena M, Balaji SA, Deshpande N. et al. AMP-activated protein kinase promotes epithelial-mesenchymal transition in cancer cells through Twist1 upregulation. J Cell Sci 2018; 131: jcs208314
    PubMedGoogle Scholar
  • 23 Laderoute KR, Calaoagan JM, Chao WR. et al. 5′-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors. J Biol Chem 2014; 289: 22850-22864
    CrossrefPubMedGoogle Scholar
  • 24 Jacobsen LV, Flint A, Olsen AK. et al. Liraglutide in type 2 diabetes mellitus: Clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2016; 55: 657-672
    CrossrefPubMedGoogle Scholar
  • 25 Saxena M, Stephens MA, Pathak H. et al. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis 2011; 2: e179
    CrossrefPubMedGoogle Scholar
  • 26 Ding XW, Wu JH, Jiang CP. ABCG2: A potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci 2010; 86: 631-637
    CrossrefPubMedGoogle Scholar
  • 27 Mato E, Gonzalez C, Moral A. et al. ABCG2/BCRP gene expression is related to epithelial-mesenchymal transition inducer genes in a papillary thyroid carcinoma cell line (TPC-1). J Mol Endocrinol 2014; 52: 289-300
    CrossrefPubMedGoogle Scholar