Evaluation the interaction of ABC multidrug transporter MDR1 with thymoquinone: substrate or inhibitor?

Document Type : Original Article

Authors

1 Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran

2 Department of Biotechnology and Plant Breeding, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran

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

4 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Irann

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

6 Department of Biology, Faculty of Sciences, University of Sistan and Baluchestan, Zahedan, Iran

Abstract

Objective(s): Thymoquinone (TQ) has valuable medical properties like anticancer effects. Development of multidrug resistance (MDR) phenotype is one of the most important factors in failure of cancer chemotherapy. The aim of this study was to evaluate the mode of interaction of TQ and MDR1, a major MDR-related protein in gastric cancer drug resistant EPG85-257RDB cells, and its parental non-resistant EPG85-257 cells.
Materials and Methods: MTT assay was used to assess the effects of TQ and doxorubicin (DOX) on cell viability of tested cell lines and TQ effect on pump performance. HPLC analyses were used to measure the input and output of TQ in EPG85-257RDB cells. Molecular docking studies were used to identify interactions between TQ and MDR1.
Results: TQ inhibited cell viability in a time and concentration-dependent manner. Co-treatment of the cells with TQ and DOX did not significantly affect the amount of cell viability in comparison with DOX treatment alone. The HPLC analyses showed that more than 90% of TQ entered to EPG85-257RDB during 1 hr of treatment with TQ, but it was unable to exit from the cells. Moreover, there was no difference between influx and efflux amount of TQ in cells with inhibited and non-inhibited MDR1 transporters. Molecular docking studies revealed that TQ had a higher inhibitory constant to bind to active site of MDR1 protein as compared to specific inhibitor (verapamil) and substrate (vinblastine) of this transporter.
Conclusion: These results proposed that TQ does not work as an inhibitor or a substrate of MDR1 transporter.

Keywords

References

1. Sugimoto Y, Tsukahara S, Imai Y, Ueda K, Tsuruo T. Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists1. Mol Cancer Ther 2003;2:105-112.
2. Bodó A, Bakos É, Szeri F, Váradi A, Sarkadi B. The role of multidrug transporters in drug availability, metabolism and toxicity. Toxicol Lett 2003;140:133-143.
3. Neyshaburinezhad N, Hashemi M, Ramezani M, Arabzadeh S, Behravan J, Kalalinia F. The effects of crocetin, extracted from saffron, in chemotherapy against the incidence of multiple drug resistance phenotype. Iran J Basic Med Sci 2018;21:1192-1197.
4. Pop RM, Trifa AP, Popolo A, Chedea VS, Militaru C, Bocsan IC, et al. Nigella sativa: Valuable perspective in the management of chronic diseases. Iran J Basic Med Sci 2020;23:699-713.
5. Rooney S, Ryan M. Effects of alpha-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer Res 2005;25:2199-21204.
6. Wu Z, Chen Z, Shen Y, Huang L, Jiang P. Anti-metastasis effect of thymoquinone on human pancreatic cancer. Yao Xue Xue Bao 2011;46:910-914.
7. Jafri SH, Glass J, Shi R, Zhang S, Prince M, Kleiner-Hancock H. Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo. J Exp Clin Cancer Res 2010;29:87.
8. Ahmad A, Mishra RK, Vyawahare A, Kumar A, Rehman MU, Qamar W, et al. Thymoquinone (2-Isoprpyl-5-methyl-1, 4-benzoquinone) as a chemopreventive/anticancer agent: Chemistry and biological effects. Saudi Pharm J 2019;27:1113-1126.
9. Effenberger-Neidnicht K, Schobert R. Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin. Cancer Chemother Pharmacol 2011;67:867-874.
10. Kouidhi B, Zmantar T, Jrah H, Souiden Y, Chaieb K, Mahdouani K, et al. Antibacterial and resistance-modifying activities of thymoquinone against oral pathogens. Ann Clin Microbiol Antimicrob. 2011;10:29-35.
11. Worthen DR, Ghosheh OA, Crooks P. The in vitro anti-tumor activity of some crude and purified components of blackseed, Nigella sativa L. Anticancer Res 1998;18:1527-1532.
12. Kalalinia F, Elahian F, Hassani M, Kasaeeian J, Behravan J. Phorbol ester TPA modulates chemoresistance in the drug sensitive breast cancer cell line MCF-7 by inducing expression of drug efflux transporter ABCG2. Asian Pac J Cancer Prev 2012;13:2979-2984.
13. Kalalinia F, Elahian F, Mosaffa F, Behravan J. Celecoxib up regulates the expression of drug efflux transporter ABCG2 in breast cancer cell lines. Iran J Pharm Res 2014;13:1393-1401.
14. Abdelmeguid NE, Fakhoury R, Kamal SM, Al Wafai RJ. Effects of Nigella sativa and thymoquinone on biochemical and subcellular changes in pancreatic β‐cells of streptozotocin‐induced diabetic rats. J Diabetes 2010;2:256-266.
15. Kara MI, Erciyas K, Altan AB, Ozkut M, Ay S, Inan S. Thymoquinone accelerates new bone formation in the rapid maxillary expansion procedure. Arch Oral Biol 2012;57:357-363.
16. Alaufi OM, Noorwali A, Zahran F, Al-Abd AM, Al-Attas S. Cytotoxicity of thymoquinone alone or in combination with cisplatin (CDDP) against oral squamous cell carcinoma in vitro. Sci Rep 2017;7:13131-13142.
17. Stein U, Lage H, Jordan A, Walther W, Bates SE, Litman T, et al. Impact of BCRP/MXR, MRP1 and MDR1/P‐glycoprotein on thermoresistant variants of atypical and classical multidrug resistant cancer cells. Int J Cancer 2002;97:751-760.
18. Alemi M, Sabouni F, Sanjarian F, Haghbeen K, Ansari S. Anti-inflammatory effect of seeds and callus of Nigella sativa L. extracts on mix glial cells with regard to their thymoquinone content. AAPS PharmSciTech 2013;14:160-167.
19. Ghosheh OA, Houdi AA, Crooks PA. High performance liquid chromatographic analysis of the pharmacologically active quinones and related compounds in the oil of the black seed (Nigella sativa L.). J Pharm Biomed Anal 1999;19:757-762.


Iranian Journal of Basic Medical Sciences
Volume 23, Issue 10
October 2020
Pages 1360-1366

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