THE MODULATION OF DRUG EFFLUX TRANSPORTER BY CURCUMIN IN MCF7 BREAST CANCER CELLS AFTER REPEATED EXPOSURE OF ENDOXIFEN AND ESTRADIOL
Objective: The aim of the present study was to determine whether curcumin (CM) can prevent drug sensitivity of breast cancer (BC) cells when E and
Î²-E2 are administered together and whether the underlying mechanism involves modulation of drug efflux transporters.
Methods: MCF7 BC cells were treated with the vehicle only, E+Î²-E2, or E+Î²-E2+CM repeatedly for 8 weeks. Afterward, the cells were harvested,
counted, and isolated for total RNA extraction. Total RNA was then processed into cDNA and further processed for the determination of mRNA
expression patterns of drug efflux transporters (P-glycoprotein, BCRP, and MRP1).
Results: Decreased sensitivity of BC cells was shown by the increased cell viability of MCF7 cells after 8 weeks. This condition was accompanied with
increased mRNA expression of P-glycoprotein, BCRP, and MRP1 in cells treated with E+Î²-E2, as compared with the vehicle only. CM, administered in
combination with E+Î²-E2, resulted in decreased cell viability versus E and Î²-E2 and also decreased in mRNA expression of P-glycoprotein, BCRP, and
Conclusion: CM partially reversed the sensitivity loss of BC cells to E in the presence of Î²-E2 by modulating drug efflux transporters.
versus tamoxifen for advanced breast cancer. Cochrane Database Syst
2. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive
evaluation of tamoxifen sequential biotransformation by the human
cytochrome P450 system in vitro: Prominent roles for CYP3A and
CYP2D6. J Pharmacol Exp Ther 2004;310:1062-75.
3. Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC,
et al. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that
targets estrogen receptor alpha for degradation in breast cancer cells.
Cancer Res 2009;69:1722-7.
4. Hawse JR, Subramaniam M, Cicek M, Wu X, Gingery A, Grygo SB,
et al. Endoxifenâ€™s molecular mechanisms of action are concentration
dependent and different than that of other anti-estrogens. PLoS One
5. Dixon JM. Endocrine resistance in breast cancer. N J Sci 2014;2014:1â€‘27.
6. Hawse JR, Subramaniam M, Wu X, Negron V, Muzaffer C, Lingle WL,
et al. Abstract PD05-11: Development, characterization, and effective
in vitro treatment of an endoxifen resistant breast cancer cell line.
Cancer Res 2010;70:PD05-11.
7. Paramita P, Louisa M, Nafrialdi N. Increased vimentin mRNA
expression in MCF-7 breast cancer cell line after repeated endoxifentreatment.
Med J Indones 2016;25:207-13.
8. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast
cancer. Annu Rev Med 2011;62:233-47.
9. Krisnamurti DG, 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.
10. Choi HK, Yang JW, Roh SH, Han CY, Kang KW. Induction of
multidrug resistance associated protein 2 in tamoxifen-resistant breast
cancer cells. J Pharmacol Exp Ther 2002;302:407-15.
11. Iusuf D, Teunissen SF, Wagenaar E, Rosing H, Beijnen JH, Schinkel AH,
et al. P-glycoprotein (ABCB1) transports the primary active tamoxifen
metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain
penetration. J Pharmacol Exp Ther 2011;337:710-7.
12. Xue X, Yu JL, Sun DQ, Zhou W, Kong F, Wu J, et al. Curcumin as
a multidrug resistance modulator-a quick review. Biomed Prev Nutr
13. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: From ancient
medicine to current clinical trials. Cell Mol Life Sci 2008;65:1631-52.
14. Squirewell EJ, Duffel MW. The effects of endoxifen and other major
metabolites of tamoxifen on the sulfation of estradiol catalyzed by
human cytosolic sulfotransferases hSULT1E1 and hSULT1A11. Drug
Metab Dispos 2015;43:843-50.
15. Teft WA, Mansell SE, Kim RB. Endoxifen, the active metabolite of
tamoxifen, is a substrate of the efflux transporter P-glycoprotein
(multidrug resistance 1). Drug Metab Dispos 2011;39:558-62.
16. Louisa M, Sugiarti L, Kurniawan SV, Wanandi SI. Curcumin increases
anti-cancer activity of tamoxifen in MCF-7 breast cancer cells
through the suppression of MDR1 mRNA expression. Adv Sci Lett
17. Alavala RR, Katahala P, Thipparapu G, Kulandaivelu U, Boyapati S,
Mantripragada BR. Study in vivo pharmacokinetic drug interactions of
curcumin on tacrine. Asian J Pharm Clin Res 2018;11:337-43.
18. Gadekar R, Saurabh MK, Thakur GS, Saurabh A. Study of formulation,
characterisation and wound potential of transdermal patches of
curcumin. Asian J Pharm Clin Res 2012;5:225-30.
19. Leslie EM, Deeley RG, Cole SP. Bioflavonoid stimulation of glutathione
transport by the 190-kDa multidrug resistance protein 1 (MRP1). Drug
Metab Dispos 2003;31:11-5.