The effects of crocetin, extracted from saffron, in chemotherapy against the incidence of multiple drug resistance phenotype

Document Type: Short Communication

Authors

1 Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

2 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

5 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Crocetin, one of the main substances of saffron extract, has anti-cancer effects. Drug resistance proteins (e.g. MRP1 and MRP2) are important reasons for the failure of cancer therapy. We intended to investigate the efficacy of crocetin on MRP1 and MRP2 activity in human ovarian cisplatin-resistant carcinoma cell line (A2780-RCIS).
Materials and Methods: The cytotoxic effect of crocetin was evaluated by the MTT assay. The efficacy of crocetin on MRP1 and MRP2 expression at mRNA level was studied by real-time RT-PCR. The effect of crocetin on the activity of MRP transporters was determined by drug efflux assay.
Results: Crocetin decreased cell proliferation in the A2780 (IC50: 183±7 µM) and A2780-RCIS (IC50: 316±9 µM). Crocetin decreased the expression level of MRP1 (22±2 %) and MRP2 (48±8 %) in A2780-RCIS and inhibited MRP pumps function directly in A2780 (44±1 %) and A2780-RCIS (88±10 %) and indirectly in A2780 (32±2 %) and A2780-RCIS (48±15 %) respectively.
Conclusion: Our findings showed that crocetin could quench drug resistance through modulation of MRP transporters in the drug resistant human ovarian cancer cells.

Keywords

Main Subjects


1. Zare-Shahabadi A, Langroodi HG, Azimi AR, Sahraian MA, Harirchian MH, Baghbanian SM. Neuromyelitis optica and pregnancy. Acta Neurol Belg. 2016;116:431-438.
2. Violette PD, Saad F. Chemoprevention of prostate cancer: myths and realities. J Am Board Fam Med. 2012;25:111-119.
3. Schuster M, Nechansky A, Kircheis R. Cancer immunotherapy. Biotechnol J. 2006;1:138-147.
4. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci. 2000;11:265-283.
5. Eckford PD, Sharom FJ. ABC efflux pump-based resistance to chemotherapy drugs. Chem Rev. 2009;109:2989-3011.
6. Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC. The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. Br J Pharmacol. 1999;128:563-568.
7. HemaIswarya S, Doble M. Potential synergism of natural products in the treatment of cancer. Phytother Res. 2006;20:239-249.
8. Abe K, Saito H. Effects of saffron extract and its constituent crocin on learning behaviour and long-term potentiation. Phytother Res. 2000;14:149-152.
9. Srivastava R, Ahmed H, Dixit RK, Dharamveer, Saraf SA. Crocus sativus L.: A comprehensive review. Pharmacogn Rev. 2010;4:200-208.
10. Zarei Jaliani H, Riazi GH, Ghaffari SM, Karima O, Rahmani A. The effect of the crocus sativus L. Carotenoid, crocin, on the polymerization of microtubules, in vitro. Iran J Basic Med Sci. 2013;16:101-107.
11. Mahdizadeh S, Karimi G, Behravan J, Arabzadeh S, Lage H, Kalalinia F. Crocin suppresses multidrug resistance in MRP overexpressing ovarian cancer cell line. Daru. 2016;24:17.
12. Giaccio M. Crocetin from saffron: an active component of an ancient spice. Crit Rev Food Sci Nutr. 2004;44:155-172.
13. Gutheil WG, Reed G, Ray A, Anant S, Dhar A. Crocetin: an agent derived from saffron for prevention and therapy for cancer. Curr Pharm Biotechnol. 2012;13:173-179.
14. Kim SH, Lee JM, Kim SC, Park CB, Lee PC. Proposed cytotoxic mechanisms of the saffron carotenoids crocin and crocetin on cancer cell lines. Biochem Cell Biol. 2014;92:105-111.
15. Timm M, Saaby L, Moesby L, Hansen EW. Considerations regarding use of solvents in in vitro cell based assays. Cytotechnology. 2013;65:887-894.
16. Anger GJ, Cressman AM, Piquette-Miller M. Expression of ABC Efflux transporters in placenta from women with insulin-managed diabetes. PLoS One. 2012;7:e35027.
17. Gotze S, Feldhaus V, Traska T, Wolter M, Reifenberger G, Tannapfel A, et al. ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma. BMC Cancer. 2009;9:447.
18. Yamaguchi S, Zhao YL, Nadai M, Yoshizumi H, Cen X, Torita S, et al. Involvement of the drug transporters p glycoprotein and multidrug resistance-associated protein Mrp2 in telithromycin transport. Antimicrob Agents Chemother. 2006;50:80-87.
19. Janneh O, Jones E, Chandler B, Owen A, Khoo SH. Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother. 2007;60:987-993.
20. Huang M, Liu G. The study of innate drug resistance of human hepatocellular carcinoma Bel7402 cell line. Cancer Lett. 1999;135:97-105.
21. Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc). 2000;65:95-106.
22. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Exp Biol Med (Maywood). 2002;227:20-25.
23. Cui Y, Konig J, Buchholz JK, Spring H, Leier I, Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol. 1999;55:929-937.
24. Koike K, Kawabe T, Tanaka T, Toh S, Uchiumi T, Wada M, et al. A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. Cancer Res. 1997;57:5475-5479.
25. Gyemant N, Tanaka M, Molnar P, Deli J, Mandoky L, Molnar J. Reversal of multidrug resistance of cancer cells in vitro: modification of drug resistance by selected carotenoids. Anticancer Res. 2006;26:367-374.
26. Shen J, Cross ST, Tang-Liu DD, Welty DF. Evaluation of an immortalized retinal endothelial cell line as an in vitro model for drug transport studies across the blood-retinal barrier. Pharm Res. 2003;20:1357-1363.
27. Eid SY, El-Readi MZ, Wink M. Carotenoids reverse multidrug resistance in cancer cells by interfering with ABC-transporters. Phytomedicine. 2012;19:977-987.
28. Zhong YJ, Shi F, Zheng XL, Wang Q, Yang L, Sun H, et al. Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms. Acta Pharmacol Sin. 2011;32:1529-1536.