Objective: To explore the effects and mechanism of glycogen synthase kinase 3β (GSK-3β) inhibitor (2'Z,3'E)-6-bromo-indirubin-3'-oxime (BIO) on drug resistance in colon cancer cells.Methods: The colon cancer SW480 and SW620 cells were treated with BIO, 5-fluorouracil (5-FU) and BIO/5-FU, separately. Cell cycle distribution, apoptosis level and efflux ability of rhodamine 123 (Rh123) were detected by flow cytometry. The protein expressions of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2), thymidylate synthase (TS), β-catenin, E2F-1 and Bcl-2 were detected by Western blot. β-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope.Results: BIO up-regulated β-catenin, P-gp, MRP2 and TS, enhanced the efflux ability of Rh123, decreased Bcl-2 protein and gave the opposite effect to E2F-1 protein in SW480 and SW620 cells. Furthermore, BIO significantly inhibited cell apoptosis, increased S and G 2
It had been found that interleukin-8 (IL-8) was associated with drug resistance. We previously demonstrated that the resistance to 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) of glioma cell line SWOZ1 was much higher than that of cell line SOWZ2, which were both cloned from the same parental glioma cell line SWO38. In this study, IL-8 was found to be upregulated both in SWOZ1 and SWOZ2-BCNU, a BCNU-resistant glioma cell line. To further investigate the function of IL-8, the BCNU-resistant cell lines SWOZ1 and SWOZ2-BCNU were treated with siRNAs targeting IL-8. The results of quantitative RT-PCR showed that a decreased level of IL-8 mRNA expression in SWOZ1 and SWOZ2-BCNU for more than 90% compared to negative control and was confirmed by western blot assay (P < 0.05) after treated by siRNAs targeting IL-8. Subsequently, the cytotoxicity of BCNU to these cell lines was detected using the cell counting kit-8 assay. As a result, the BCNU resistance was reversed for about 50% both in these two cell lines (P < 0.05). Our data demonstrated that inhibition of IL-8 with specific siRNAs can reverse the BCNU resistant phenotype in glioma cell lines, indicating that IL-8 may play an important role in BCNU-resistance in glioma.
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