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

Abstract

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. IntroductionResveratrol belongs to the stilbenoid group of polyphenols, possessing two phenol rings linked to each other by an ethylene bridge (1). In 1940, resveratrol was isolated from the root of Veratrum grandiflorum (1,2). A primary dietary source of resveratrol is red wine, as a very high resveratrol concentration is present in the skin of red grapes (50-100 µg/g) (3). In natural conditions, resveratrol is synthesized by plants in response to external environmental factors, including ultraviolet radiation and heavy metals (3,4). Resveratrol is identified in two isomeric forms, cis and trans-resveratrol ( Fig. 1) (5,6).The trans form is dominant in terms of its prevalence and biological activity (7). The hydrophobic nature of resveratrol considerably contributes to its limited bioavailability (8).Owing to the varied biological activity of resveratrol, it has been the subject of numerous studies aimed at revealing its health-enhancing properties, and its use in prevention and treatment of many diseases (1,3,5,9). The results of in vitro and in vivo studies have proved that resveratrol exhibits anticancer activity at all three stages of the oncogenic process: initiation, promotion and progr...

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