Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

Mieszala,Katarzyna; Rudewicz,Malgorzata; Gomulkiewicz,Agnieszka; Ratajczak‑Wielgomas,Katarzyna; Grzegrzolka,Jedrzej; Dziegiel,Piotr; Borska,Sylwia

doi:10.3892/ol.2018.8022

Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

Authors:
- Katarzyna Mieszala
- Malgorzata Rudewicz
- Agnieszka Gomulkiewicz
- Katarzyna Ratajczak‑Wielgomas
- Jedrzej Grzegrzolka
- Piotr Dziegiel
- Sylwia Borska
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Affiliations: Department of Histology and Embryology, Wroclaw Medical University, 50‑368 Wroclaw, Poland
Published online on: February 12, 2018 https://doi.org/10.3892/ol.2018.8022
Pages: 5825-5832

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Abstract

Multidrug resistance (MDR) is a notable problem in the use of chemotherapy. Therefore, studies aimed at identifying substances capable of overcoming resistance of cancer cells are required. Examples of these compounds are polyphenols, including resveratrol, that exert a range of various biological activities. The aim of the present study was to demonstrate the effect of 3,5,4'‑trihydroxy‑trans‑stilbene (resveratrol) on the expression of ATP binding cassette subfamily B member 1, Annexin A1 (ANXA1) and thioredoxin (TXN) genes, and the proteins encoded by these genes, which are associated with MDR. The experiments were performed in human gastric cancer cell lines EPG85‑257RDB (RDB) and EPG85‑257RNOV (RNOV), which are resistant to daunorubicin and mitoxantrone, respectively, in addition to EPG85‑257P (control), which is sensitive to cytostatic drugs. Cells were treated with 30 or 50 µM resveratrol for 72 h and changes in the expression levels of the genes were analysed with the use of a reverse transcription‑quantitative polymerase chain reaction. The cellular levels of P‑glycoprotein (P‑gp), ANXA1 and TXN were evaluated using immunofluorescence and western blot analysis. Resveratrol in both concentrations has been shown to have a statistically significant influence on expression of the mentioned genes, compared with untreated cells. In RDB cells, resveratrol reduced the expression level of all analyzed genes, compared with untreated cells. Similar results at the protein level were obtained for P‑gp and TXN. In turn, in the RNOV cell line, resveratrol reduced TXN expression at mRNA and protein levels, compared with untreated cells. The results of the present study indicate that resveratrol may reduce the resistance of cancer cells by affecting the expression of a number of the genes and proteins associated with MDR.

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1	Tomé-Carneiro J, Larrosa M, González-Sarrías A, Tomás-Barberán FA, García-Conesa MT and Espín JC: Resveratrol and clinical trials: The crossroad from in vitro studies to human evidence. Curr Pharm Des. 19:6064–6093. 2013. View Article : Google Scholar : PubMed/NCBI
2	Nakata R, Takahashi S and Inoue H: Recent advances in the study on resveratrol. Biol Pharm Bull. 35:273–279. 2012. View Article : Google Scholar : PubMed/NCBI
3	Gupta C and Prakash D: Phytonutrients as therapeutic agents. J Complement Integr. 11:151–169. 2014.
4	Athar M, Back JH, Kopelovich L, Bickers DR and Arianna L: Multiple molecular targets of resveratrol: Anti carcinogenic mechanisms. Arch Biochem Biophys. 486:95–102. 2010. View Article : Google Scholar
5	Aguirre L, Fernández-Quintela A, Arias N and Portillo MP: Resveratrol: Anti-obesity mechanisms of action. Molecules. 19:18632–18655. 2014. View Article : Google Scholar : PubMed/NCBI
6	Sinha D, Sarkar N, Biswas J and Bishayee A: Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms. Semin Cancer Biol 40–41. 1–232. 2016.
7	Rodríguez-Cabo T, Rodríguez I, Ramil M and Cela R: Comprehensive evaluation of the photo-transformation routes of trans-resveratrol. J Chromatogr A. 1410:129–139. 2015. View Article : Google Scholar : PubMed/NCBI
8	Trollope L, Cruickshank DL, Noonan T, Bourne SA, Sorrenti M, Catenacci L and Caira MR: Inclusion of trans-resveratrol in methylated cyclodextrins: Synthesis and solid-state structures. Beilstein J Org Chem. 10:3136–3151. 2014. View Article : Google Scholar : PubMed/NCBI
9	Lançon A, Michaille JJ and Latruffe N: Effects of dietary phytophenols on the expression of microRNAs involved in mammalian cell homeostasis. J Sci Food Agric. 93:3155–3164. 2013. View Article : Google Scholar : PubMed/NCBI
10	Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, et al: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 275:218–220. 1997. View Article : Google Scholar : PubMed/NCBI
11	Liu T, Liu X and Li W: Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy. Oncotarget. 26:40800–40815. 2016.
12	Gilmore TD and Herscovitch M: Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene. 25:6887–6899. 2006. View Article : Google Scholar : PubMed/NCBI
13	Liu Y, Li Q, Zhou L, Xie N, Nice EC, Zhang H, Huang C and Lei Y: Cancer drug resistance: Redox resetting renders a way. Oncotarget. 7:42740–42761. 2016.PubMed/NCBI
14	Kartal-Yandim M, Adan-Gokbulut A and Baran Y: Molecular mechanisms of drug resistance and its reversal in cancer. Crit Rev Biotechnol. 36:716–726. 2016.PubMed/NCBI
15	Nieth C, Priebsch A, Stege A and Lage H: Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi). FEBS Lett. 545:144–150. 2003. View Article : Google Scholar : PubMed/NCBI
16	Abdallah HM, Al-Abd AM, El-Dine RS and El-Halawany AM: P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review. J Adv Res. 6:45–62. 2015. View Article : Google Scholar : PubMed/NCBI
17	Wu CP and V Ambudkar S: The pharmacological impact of ATP-binding cassette drug transporters on vemurafenib-based therapy. Acta Pharm Sin B. 4:105–111. 2014. View Article : Google Scholar : PubMed/NCBI
18	Kapse-Mistry S, Govender T, Srivastava R and Yergeri M: Nanodrug delivery in reversing multidrug resistance in cancer cells. Front Pharmacol. 5:1592014.PubMed/NCBI
19	Borska S, Chmielewska M, Wysocka T, Drag-Zalesinska M, Zabel M and Dziegiel P: In vitro effect of quercetin on human gastric carcinoma: Targeting cancer cells death and MDR. Food Chem Toxicol. 50:3375–3383. 2012. View Article : Google Scholar : PubMed/NCBI
20	Karthikeyan S, Hoti SL and Prasad NR: Resveratrol modulates expression of ABC transporters in non-small lung cancer cells: Molecular docking and gene expression studies. Cancer Sci Ther. 6:497–504. 2014.
21	Chen Z, Shi T, Zhang L, Zhu P, Deng M, Huang C, Hu T, Jiang L and Li J: Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 370:153–164. 2016. View Article : Google Scholar : PubMed/NCBI
22	Levatić J, Ćurak J, Kralj M, Šmuc T, Osmak M and Supek F: Accurate models for P-gp drug recognition induced from a cancer cell line cytotoxicity screen. J Med Chem. 56:5691–5708. 2013. View Article : Google Scholar : PubMed/NCBI
23	Lopes-Rodrigues V, Seca H, Sousa D, Sousa E, Lima RT and Vasconcelos MH: The network of P-glycoprotein and microRNAs interactions. Int J cancer. 15135:253–263. 2014. View Article : Google Scholar
24	Belvedere R, Bizzarro V, Forte G, Dal Piaz F, Parente L and Petrella A: Annexin A1 contributes to pancreatic cancer cell phenotype, behaviour and metastatic potential independently of Formyl Peptide Receptor pathway. Sci Rep. 6:296602016. View Article : Google Scholar : PubMed/NCBI
25	Gao Y, Chen Y, Xu D, Wang J and Yu G: Differential expression of ANXA1 in benign human gastrointestinal tissues and cancers. BMC Cancer. 14:5202014. View Article : Google Scholar : PubMed/NCBI
26	Wang Y, Serfass L, Roy MO, Wong J, Bonneau AM and Georges E: Annexin-I expression modulates drug resistance in tumor cells. Biochem Biophys Res Commun. 314:565–570. 2004. View Article : Google Scholar : PubMed/NCBI
27	Powis G, Mustacich D and Coon A: The role of the redox protein thioredoxin in cell growth and cancer. Free Radic Biol Med. 29:312–322. 2000. View Article : Google Scholar : PubMed/NCBI
28	Reuter S, Gupta SC, Park B, Goel A and Aggarwal BB: Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr. 6:93–108. 2011. View Article : Google Scholar : PubMed/NCBI
29	Borska S, Owczarek M, Pedziwiatr M, Gomulkiewicz A, Pula B and Dziegiel P: (unpublished report): In vitro studies of pleiotropic effects of resveratrol on cancer cells resistant to cytostatics. Wisla. 2014.
30	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
31	Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 227:680–685. 1970. View Article : Google Scholar : PubMed/NCBI
32	Moitra K: Overcoming multidrug resistance in cancer stem cells. Biomed Res Int. 2015:6357452015. View Article : Google Scholar : PubMed/NCBI
33	Kunjachan S, Rychlik B, Storm G, Kiessling F and Lammers T: Multidrug resistance: Physiological principles and nanomedical solutions. Adv Drug Deliv Rev. 65:1852–1865. 2013. View Article : Google Scholar : PubMed/NCBI
34	Long S, Sousa E, Kijjoa A and Pinto MM: Marine natural products as models to circumvent multidrug resistance. Molecules. 21:E8922016. View Article : Google Scholar : PubMed/NCBI
35	Lopes-Rodrigues V, Di Luca A, Sousa D, Seca H, Meleady P, Henry M, Lima RT, O'Connor R and Vasconcelos MH: Multidrug resistant tumour cells shed more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart cells. Biochim Biophys Acta. 1860:618–627. 2016. View Article : Google Scholar : PubMed/NCBI
36	Borska S, Pedziwiatr M, Danielewicz M, Nowinska K, Pula B, Drag-Zalesinska M, Olbromski M, Gomulkiewicz A and Dziegiel P: Classical and atypical resistance of cancer cells as a target for resveratrol. Oncol Rep. 36:1562–1568. 2016. View Article : Google Scholar : PubMed/NCBI
37	Lu JJ, Cai YJ and Ding J: The short-time treatment with curcumin sufficiently decreases cell viability, induces apoptosis and copper enhances these effects in multidrug-resistant K562/A02 cells. Mol Cell Biochem. 360:253–260. 2012. View Article : Google Scholar : PubMed/NCBI
38	Eid SY, El-Readi MZ, Eldin EE, Fatani SH and Wink M: Influence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells. Phytomedicine. 21:47–61. 2013. View Article : Google Scholar : PubMed/NCBI
39	Wang Z, Zhang L, Ni Z, Sun J, Gao H, Cheng Z, Xu J and Yin P: Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L-OHP cells by preventing activation of NF-κB signaling and suppressing cAMP-responsive element transcriptional activity. Tumor Biol. 36:9499–9510. 2015. View Article : Google Scholar
40	Quan F, Pan C, Ma Q, Zhang S and Yan L: Reversal effect of resveratrol on multidrug resistance in KBv200 cell line. Biomed Pharmacother. 62:622–629. 2008. View Article : Google Scholar : PubMed/NCBI
41	El-Araby ME, Omar AM, Khayat MT, Assiri HA and Al-Abd AM: Molecular mimics of classic p-glycoprotein inhibitors as multidrug resistance suppressors and their synergistic effect on paclitaxel. PLoS One. 12:e01689382017. View Article : Google Scholar : PubMed/NCBI
42	Li G, He S, Chang L, Lu H, Zhang H, Zhang H and Chiu J: GADD45α and annexin A1 are involved in the apoptosis of HL-60 induced by resveratrol. Phytomedicine. 18:704–709. 2011. View Article : Google Scholar : PubMed/NCBI
43	Alldridge LC and Bryant CE: Annexin 1 regulates cell proliferation by disruption of cell morphology and inhibition of cyclin D1 expression through sustained activation of the ERK1/2 MAPK signal. Exp Cell Res. 290:93–107. 2003. View Article : Google Scholar : PubMed/NCBI
44	Solito E, de Coupade C, Canaider S, Goulding NJ and Perretti M: Transfection of annexin 1 in monocytic cells produces a high degree of spontaneous and stimulated apoptosis associated with caspase-3 activation. Br J Pharmacol. 133:217–228. 2001. View Article : Google Scholar : PubMed/NCBI
45	Debret R, El Btaouri H, Duca L, Rahman I, Radke S, Haye B, Sallenave JM and Antonicelli F: Annexin A1 processing is associated with caspase-dependent apoptosis in BZR cells. FEBS Lett. 546:195–202. 2003. View Article : Google Scholar : PubMed/NCBI
46	Sinha P, Hütter G, Köttgen E, Dietel M, Schadendorf D and Lage H: Increased expression of annexin I and thioredoxin detected by two-dimensional gel electrophoresis of drug resistant human stomach cancer cells. J Biochem Biophys Methods. 37:105–116. 1998. View Article : Google Scholar : PubMed/NCBI
47	Karlenius TC and Tonnisen KF: Thioredoxin and cancer: A role for thioredoxin in all states of tumor oxygenation. Cancers (Basel). 2:209–232. 2010. View Article : Google Scholar : PubMed/NCBI
48	Li C, Thompson MA, Tamayo AT, Zuo Z, Lee J, Vega F, Ford RJ and Pham LV: Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma. Oncotarget. 33:314–326. 2012.
49	Tonissen KF and Di Trapani G: Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy. Mol Nutr Food Res. 53:87–103. 2009. View Article : Google Scholar : PubMed/NCBI
50	Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K and Ichijo H: Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17:2596–2606. 1998. View Article : Google Scholar : PubMed/NCBI