CURCUMIN INCREASES THE SENSITIVITY OF BREAST CANCER CELLS TO TAMOXIFEN BY INHIBITING MRP2 MRNA EXPRESSION OF EFFLUX TRANSPORTER MRP2
Objective: Tamoxifen is the drug of choice to treat breast cancer positive for estrogen receptor. Long-term use of tamoxifen can induce multidrug resistance (MDR) associated with decreased sensitivity of cancer cells to the drug. One of the causes of MDR is overexpression of efflux transporter multidrug resistance-associated protein (MRP)2. Various drugs are known to act as MRP2 inhibitors, including curcumin. This study investigated the effects of curcumin on the sensitivity of breast cancer cells to tamoxifen through inhibition of MRP2.
Methods: We used MCF-7 cells that were previously exposed to long-term tamoxifen treatment [MCF-7(T) cells]. MCF-7(T) cells were treated with 1 µM tamoxifen, curcumin (5, 10, and 20 µM), combinations of curcumin (5, 10, and 20 µM) and 1 µM tamoxifen, or 10 µM nevirapine (a known MRP2 inhibitor) for 5 d. Then, the cells were harvested, counted to assess cell viability, and evaluated for MRP2 mRNA expression.
Results: Treatment with curcumin alone or in combination with tamoxifen significantly reduced cell viability at all curcumin concentrations compared with the control. The reduction in cell viability was accompanied by a reduced level of MRP2 mRNA expression.
Conclusion: Application of curcumin to MCF-7 cells previously exposed to long-term tamoxifen treatment increase the sensitivity of cancer cells to tamoxifen. The increased sensitivity of these cells was attributed, at least in part, to inhibition of the efflux transporter MRP2.
2. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporter. Nat Rev Can 2002;2:48-58.
3. Choi CH. ABC transporter as multidrug resistance mechanism and the development of chemosensitizers for their reversal. Cancer Cell Int 2005;5:30.
4. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, et al. Drug resistance in cancer: an overview. Cancers (Basel) 2014;6:1769-92.
5. Chang G. Multidrug resistance ABC transporters. FEBS Lett 2003;555:102–5.
6. Wu CP, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol 2008;1:93-105.
7. Di Pietro A, Conseil G, Perez Victoria JM, Dayan G, Baubichon Cortaya H, Trompiera D, et al. Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol Life Sci 2002;59:307-22.
8. Calabrese V, Bates TE, Mancuso C. Curcumin and the cellular stress response in free radical-related diseases. Mol Nutr Food Res 2008;52:1062-73.
9. Vallianou NG, Evangelopoulos A, Schizas N. Potential anticancer properties and mechanisms of action of curcumin. Anticancer Res 2015;35:645-52.
10. Trompier D, Baubicon Cortay H, Chang XB, Maitrjean M, Barron D, Riordan JR, et al. Multiple flavonoid-binding sites within multidrug resistance protein MRP1. Cell Mol Life Sci 2003;60:2164-77.
11. Krisnamurti DGB, Louisa M, Anggraeni E, Wanandi SI. Drug efflux transporters are overexpressed in short-term tamoxifen-induced MCF7 breast cancer cells. Adv Pharmacol Sci 2016;2016:6702424.
12. Albermann N, Schmitz Winnenthal FH, Zgraggen K. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol 2005;70:949-58.
13. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2???CT method. Methods 2001;25:402-8.
14. Stavrovskaya A, Stromskaya TP. Transport proteins of the ABC family and multidrug resistance of tumor cells. Biochemistry 2008;73:592-604.
15. Choi HK, Yang JW, Roh SH, Han CY, Kang KW. Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocrine Related Cancer 2007;14:293-303.
16. Hecht M, Erber S, Harrer T, Klinker H, Roth T, Parsch H, et al. Efavirenz has the highest anti-proliferative effect of non-nucleoside reverse transcriptase inhibitors against pancreatic cancer cells. PLoS ONE 2015;10:e0130277.
17. Wu CP, Ohnuma S, Ambudkar SV. Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol 2011;12:609–20.
18. Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu H, et al. Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/lCC2 and MCF-7/lCC9. Molecules 2013;18:701-20.
19. Wortelboer HM, Usta M, Van der Velde AE, Boersma MG, Spenkelink B, van Zanden JJ, et al. Interplay between MRP inhibition and metabolism of MRP inhibitors: the case of curcumin. Chem Res Toxicol 2003;16:1642-51.
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