in vitro Modulation of P-glycoprotein, MRP-1 and BCRP Expression by Mangiferin in Doxorubicin-Treated MCF-7 Cells

  • 발행 : 2014.02.28


The multidrug resistance phenotype is one of the major problems in development of cancer cell resistance to chemotherapy. Some natural compounds from medicinal plants have demonstrated promising capacity in enhancing anticancer effects in drug resistant cancer cells. We aimed to investigate whether mangiferin might have an ability to re-sensitize MCF-7 breast cancer cells previously treated with short-term doxorubicin in vitro, through the modulation of efflux transporters, P-glycoprotein (P-gp), MRP1 and BCRP. We exposed MCF-7 breast cancer cells pretreated with doxorubicin for 10 days to mangiferin (10, 25 or 50 ${\mu}M$) for 96 hours. Afterwards, we evaluated influence on cell viability and level of mRNA expression of P-gp, MRP1 and BCRP. Doxorubicin given in combination with mangiferin at low concentrations (10 and 25 ${\mu}M$) failed to give significant reduction in cell viability, while at the highest concentrations, the combination significantly reduced cell viability. The mRNA expression analysis of P-gp, MRP1 and BCRP showed that mangiferin had inhibitory effects on P-gp but no effects on MRP1 and BCRP. In conclusion, we suggest that mangiferin at high concentrations can be used as chemosensitizer for doxorubicin therapy. This effect might be attributed by inhibitory effects of mangiferin on P-glycoprotein expression.


  1. Smith L, Watson MB, O'Kane SL, et al (2006). The analysis of doxorubicin resistance in human breast cancer cells using antibody microarrays. Mol Cancer Ther, 5, 2115-20.
  2. Sparano JA, Makhson AN, Semiglazov VF, et al (2009). Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvantadjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol, 27, 4522-9.
  3. Wind NS, Holen I (2011). Multidrug resistance in breast cancer: from in vitro models to clinical studies. Int J Breast Cancer, 2011, 967419.
  4. Wong ILK, Chan KF, Tsang KH, et al (2009). Modulation of multidrug resistance protein 1 (MRP1/ABCC1)-mediated multidrug resistance by bivalent apigenin homodimers and their derivatives. J Med Chem, 52, 5311-22.
  5. Zhang B, Fang J, Chen Y (2013). Antioxidant effect of mangiferin and its potential to be a cancer chemoprevention agent. Letters Drug Design Discovery, 10, 239-44.
  6. Zhang L, Yang Y, Wei XY, et al (2007). Reversing adriamycin resistance of human breast cancer cells by hyperthermia combined with Interferon alpha and Verapamil. J Exp Clin Cancer Res, 26, 201-7.
  7. Kars MD, Iseri OD, Gunduz U, et al (2006). Development of rational in vitro models for drug resistance in breast cancer and modulation of MDR by selected compounds. Anticancer Res, 26, 4559-68.
  8. Du Plessis-Stoman D, du Preez J, van de Venter M (2011). Combination treatment with oxaliplatin and mangiferin causes increased apoptosis and downregulation of NF${\kappa}B$ in cancer cell lines. Afr J Tradit Complement Altern Med, 8, 177-84.
  9. Farabegoli F, Papi A, Bartolini G, Ostan R, Orlandi M. (2010). (-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line. Phytomedicine, 17, 356-62.
  10. Ghebeh H, Lehe C, Barhoush E, et al (2010). Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule. Breast Cancer Res. 12, 48.
  11. Li H, Huang J, Yang B, et al (2013). Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and $\beta$-catenin signaling pathway. Toxicol Appl Pharmacol, 272, 180-90
  12. Livak KJ, Schmittgen TD, (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method Methods. 25, 402-8.
  13. Matkowski A, Kuss P, Goralska E, Wozniak D (2013). Mangiferin-a bioactive xanthonoid, not only from mango and not just antioxidant. Mini Rev Med Chem, 13, 439-55.
  14. Nabekura T (2010). Overcoming multidrug resistance in human cancer cells by natural compounds. Toxins, 2, 1207-24.
  15. Andreopoulou E, Sparano JA (2013). Chemotherapy in Patients with Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer: An Overview. Curr Breast Cancer Rep, 5, 42-50.
  16. Bruning A, Friese K, Burges A, Mylonas I (2010). Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells. Breast Cancer Res, 12, 45.
  17. Calcagno AM, Fostel JM, To KKW, et al (2008). Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes. Br J Cancer, 98, 151-24.
  18. Chieli E, Romiti N, Rodeiro I, Garrido G (2009). The in vitro effects of Mangifera indica and polyphenols derived on ABCB1/P-glycoprotein activity. Food Chem Toxicol, 47, 2703-10.
  19. Chieli E, Romiti N, Rodeiro I, Garrido G (2010). In vitro modulation of ABCB1/P-glycoprotein expression by polyphenols from Mangifera indica. Chem Biol Interact, 186, 287-94.
  20. Chien AJ, Moasser MM (2008). Cellular mechanisms of resistance to anthracyclines and taxanes in cancer: intrinsic and acquired. Semin Oncol, 35, 1-14.
  21. Choi CH (2005). ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int, 5, 30.
  22. Donmez Y, Akhmetova L, Iseri OD, Kars MD, Gunduz U (2011). Effect of MDR modulators verapamil and promethazine on gene expression levels of MDR1 and MRP1 in doxorubicinresistant MCF-7 cells. Cancer Chemother Pharmacol, 67, 823-8.
  23. Shah KA, Patel MB, Patel RJ, Parmar PK (2010). Mangifera indica (mango). Pharmacogn Rev, 4, 42-8.

피인용 문헌

  1. Establishment and Partial Characterization of an Epirubicin-Resistant Gastric Cancer Cell Line with Upregulated ABCB1 vol.15, pp.16, 2014,
  2. Mangiferin Induces Apoptosis by Regulating Bcl-2 and Bax Expression in the CNE2 Nasopharyngeal Carcinoma Cell Line vol.15, pp.17, 2014,
  3. Alkylglyceronephosphate Synthase (AGPS) Alters Lipid Signaling Pathways and Supports Chemotherapy Resistance of Glioma and Hepatic Carcinoma Cell Lines vol.15, pp.7, 2014,
  4. Breast Cancer: Major Risk Factors and Recent Developments in Treatment vol.15, pp.8, 2014,
  5. Enhanced autophagy reveals vulnerability of P-gp mediated epirubicin resistance in triple negative breast cancer cells vol.21, pp.4, 2016,
  6. MiRNAs-mediated cisplatin resistance in breast cancer vol.37, pp.10, 2016,
  7. Mangiferin and Cancer: Mechanisms of Action vol.8, pp.7, 2016,
  8. Mangiferin: a natural miracle bioactive compound against lifestyle related disorders vol.16, pp.1, 2017,
  9. Cytochrome P450 and P-Glycoprotein-Mediated Interactions Involving African Herbs Indicated for Common Noncommunicable Diseases vol.2017, pp.1741-4288, 2017,
  10. AP-2α reverses vincristine-induced multidrug resistance of SGC7901 gastric cancer cells by inhibiting the Notch pathway vol.22, pp.7, 2017,
  11. Pantoprazole Induces Apoptosis of Leukemic Cells by Inhibiting Expression of P-Glycoprotein/Multidrug Resistance-Associated Protein-1 Through PI3K/AKT/mTOR Signaling vol.33, pp.4, 2017,
  12. vol.38, pp.5, 2018,