QUERCETIN IMPROVES THE EFFICACY OF SORAFENIB IN TRIPLE NEGATIVE BREAST CANCER CELLS THROUGH THE MODULATION OF DRUG EFFLUX TRANSPORTERS EXPRESSIONS
Keywords:BCRP, MRP2, P-glycoprotein, Quercetin, Sorafenib
Objective: This study aimed to investigate whether quercetin is able to improve the efficacy of sorafenib in triple negative breast cancer cells and explore the possibility of drug efflux transporters modulation by quercetin.
Methods: We exposed MDA-MB-231, a triple negative breast cancer cell line, to several groups: sorafenib alone, quercetin alone, a combination of sorafenib-quercetin, and control. We determined cell viability over control weekly up to 4 w. At the end of the fourth week, mRNA expressions of drug efflux transporters (P-glycoprotein and breast cancer resistance protein [BCRP] and MRP2 [multidrug resistance-associated protein-2]) were examined.
Results: Sorafenib alone was shown to maintain its efficacy for only two weeks, while quercetin alone was able to maintain its effect for four weeks. A combination of sorafenib-quercetin showed the best cytotoxicity effects compared with sorafenib or quercetin alone and was able to maintain its efficacy for four weeks. There were increased mRNA expressions of P-glycoprotein, BCRP, and MRP2 after four weeks of treatment with sorafenib, while treatment with quercetin decreased the drug efflux transporters expressions. A combination of sorafenib-quercetin decreased the mRNA expressions of both P-glycoprotein and BCRP, compared with sorafenib alone.
Conclusion: We suggest that decreased expressions of both drug efflux transporters, P-glycoprotein and BCRP, mediated by quercetin ameliorate the efficacy of sorafenib in TNBC. Therefore, the addition of quercetin to sorafenib might be useful in the future in improving the therapeutic efficacy of sorafenib in triple negative breast cancer.
2. Sankaranarayanan R, Ramadas K, Qiao Y. Managing the changing burden of cancer in Asia. BMC Med 2014;12:3.
3. Bosch A, Eroles P, Zaragoza R, Vina JR, Lluch A. Triple-negative breast cancer: Molecular features, pathogenesis, treatment and current lines of research. Cancer Treat Rev 2010;36:206-15.
4. O’Reilly EA, Gubbins L, Sharma S. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin 2015;3:257-75.
5. Kalimutho M, Parsons K, Mittal D. Targeted therapies for triple-negative breast cancer: combating a stubborn disease. Trends Pharmacol Sci 2015;36:822-46.
6. Wahba HA, El-Hadaad HA. Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med 2015;12:106-16.
7. Moreno Aspitia A. Clinical overview of sorafenib in breast cancer. Future Oncol 2010;6:655-63.
8. Chen Y, Fu L. Mechanisms of acquired resistance to tyrosine kinase inhibitors. Acta Pharm Sin B 2011;1:197-207.
9. Rivera AR, Castillo Pichardo L, Gerena Y. Anti-breast cancer potential of quercetin via the Akt/AMPK/Mammalian target of rapamycin (mTOR) signaling cascade. PLoS One 2016;11:e0157251.
10. Srinivasan A, Thangavel C, Liu Y. Abstract 5560: quercetin overcomes chemotherapy resistance in triple negative breast cancer. Cancer Res 2015;75:5560.
11. Engebraaten O, Vollan HKM, Børresen-Dale AL. Triple-negative breast cancer and the need for new therapeutic targets. Am J Pathol 2013;183:1064-74.
12. Baselga J, Costa F, Gomez H. A phase 3 trial comparing capecitabine in combination with sorafenib or placebo for treatment of locally advanced or metastatic HER2-negative breast cancer (the RESILIENCE study): study protocol for a randomized controlled trial. Trials 2013;14:228.
13. Chen J, Tian CX, Yu M. Efficacy and safety profile of combining sorafenib with chemotherapy in patients with HER2-negative advanced breast cancer: a meta-analysis. J Breast Cancer 2014;17:61-8.
14. Ferrario C, Strepponi I, Esfahani K. Phase I/II Trial of sorafenib in combination with vinorelbine as first-line chemotherapy for metastatic breast cancer. PloS One 2016;11:e0167906.
15. Moreno Aspitia A, Morton RF, Hillman DW. Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North central cancer treatment group and mayo clinic trial N0336. J Clin Oncol 2009;27:11-5.
16. Bianchi G, Loibl S, Zamagni C. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs 2009;20:616-24.
17. Shibayama Y, Nakano K, Maeda H. Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib. Biol Pharm Bull 2011;34:433-5.
18. Harmsen S, Meijerman I, Maas Bakker RF. PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors. Eur J Pharm Sci 2013;48:644-9.
19. Borska S, Chmielewska M, Wysocka T. In vitro effect of quercetin on human gastric carcinoma: targeting cancer cells death and MDR. Food Chem Toxicol 2012;50:3375-83.
20. Limtraku P, Khantamat O, Pintha K. Inhibition of P-glycoprotein function and expression by kaempferol and quercetin. J Chemother 2005;17:86-95.
21. Huang WC, Hsieh YL, Hung CM. BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib. PLoS One 2013;8:e83627.
22. Agarwal S, Sane R, Ohlfest JR, Elmquist WF. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther 2011;336:223-33.
23. Lagas JS, Van Waterschoot RAB, Sparidans RW. Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther 2010;9:319-26.
24. Zhang S, Yang X, Morris ME. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol 2004;65:1208-16.
25. Van Zanden JJ, Van der Woude H, Vaessen J. The effect of quercetin phase II metabolism on its MRP1 and MRP2 inhibiting potential. Biochem Pharmacol 2007;74:345-51.
26. Srinivasan A, Thangavel C, Liu Y. Quercetin regulates ?-catenin signaling and reduces the migration of triple negative breast cancer. Mol Carcinog 2016;55:743-56.