Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

Abstract

Abstract. Many studies have demonstrated that emodin inhibits the growth and induces the apoptosis and chemosensitization of various cancer cells in animal models. The aim of this study was to investigate the molecular mechanism of the chemo-sensitization potential of emodin on gemcitabine in pancreatic cancer cell lines via inhibition of nuclear factor-κB (nF-κB). SW1990 and SW1990/GZ cells were treated with: i) emodin (20 µmol/l), ii) nF-κB inhibitor Bay 11-7082 (5 µmol/l), iii) gemcitabine (20 µmol/l), iv) pretreated with emodin for 24 h followed by coincubation with gemcitabine for 24 h, or v) pre-treated with Bay 11-7082 for 1 h followed by treatment with gemcitabine for 24 h. SW1990 and SW1990/GZ cells were also treated with emodin (20, 40 and 80 µmol/l). cellular proliferation and apoptosis were detected by the Cell Counting Kit-8 (CCK-8) assay and flow cytometry. nF-κB protein was detected by Western blotting. SW1990/GZ cell morphological changes were observed under optical and fluorescence microscopes. Emodin strongly inhibited the proliferation and induced the apoptosis of both pancreatic cancer cell lines. Furthermore, emodin combined with gemcitabine induced a higher percentage of growth inhibition and apoptosis in both pancreatic cancer cell lines compared to gemcitabine alone. Pre-treatment of SW1990/ GZ cells with Bay 11-7082 for 1 h followed by gemcitabine resulted in greater inhibitory and apoptosis rates compared to gemcitabine alone. The resistant pancreatic cell line SW1990/ GZ presented higher constitutive nF-κB protein expression compared to the SW1990 cells. emodin not only downregulated nF-κB in a dose-dependent manner in SW1990 and SW1990/GZ cells under unstimulated conditions, but also inhibited gemcitabine-induced nF-κB protein expression. emodin potentiated the antitumor effects of gemcitabine in pancreatic cancer, which was related to the down-regulation of nF-κB.

Emodin reverses gemcitabine resistance in pancreatic cancer cells via the mitochondrial apoptosis pathway in vitro

“…Emodin (6-methyl-1,3,8-tanthragallol), which is the main active monomer separated from Rheum, Polygonum, buckthorn and senna, is a tyrosine kinase II inhibitor, it has effects of anti-microbial activity (8–11), anti-inflammatory (12,13), immunosuppression (14), anti-tumor (15,16), and activity in protection of liver cells (17). Our team previously found emodin could promote apoptosis (16), and established the gemcitabine-resistance cell line SW1990/Gem, we confirmed that emodin could increase the sensibility of resistance cell line to gemcitabine through inhibiting the expression of NF-κB (18). However, it is still unclear whether emodin can reverse the gemcitabine-resistant human pancreatic cancer cells, thus this study mainly investigates the effect of emodin reversing the gemcitabine-resistance on SW1990/Gem cell line, and its possible mechanisms.…”

“…However, reports on whether emodin can reverse the chemotherapeutic drug resistance in pancreatic cancer are rare. Our group first reported that emodin sensitized resistant cell to gemcitabine through inhibiting the expression of NF-κB in SW1990/Gem cells (18). In this study, we established the gemcitabine-resistant cell line SW1990/Gem with intermittently increasing the concentration of gemcitabine in the culture medium for 10 months, then calculated the resistance index and observed cell morphology.…”

Emodin Combined with Nanosilver Inhibited Sepsis by Anti-inflammatory Protection

“…Emodin, the bio-active compound of Radix rhizoma Rhei shows multiple pharmacological values, including anti-inflammatory, anti-fibrosis, anti-tumor proliferation, anti-atherosclerotic and immunosuppressive effects (Liu et al, 2011; Pang et al, 2015; Xue, W. H. et al, 2015). Nanosilver, shows robust effects against various microorganisms, at the same time, it causes intracellular reactive oxygen species (ROS) generation, DNA damage and apoptosis with a dose-dependent response over 1μg/ml (Orta-García et al, 2015), which limits the utilization of nanosilver in vivo .…”

The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy

“…However, the activation of NF-κB by these agents was completely abrogated by the isoflavone genistein treatment in pancreatic cancer cells (69,83–85). Experimental studies also showed that down-regulation of NF-κB by nutraceutical sulfasalazine, apigenin, curcumin, or emodin could sensitize pancreatic cancer cells to chemotherapeutic agents (71,86–91). Apigenin could down-regulate NF-κB signaling (92,93) and enhance anti-tumor efficacy of chemotherapeutic agents in pancreatic cancer (71,88).…”

“…Curcumin could decrease the expression of NF-κB p50, NF-κB p65, Sp1, Sp3, and Sp4 transcription factors that are overexpressed in pancreatic cancer cells (94), and sensitize pancreatic cancer to gemcitabine and radiation in vitro and in vivo (87,95). Emodin could also suppress NF-κB signaling (96) and sensitize gemcitabine-resistant pancreatic cancer cells to gemcitabine therapy via inhibition of MDR-1, NF-κB and its target genes, VEGF, MMP-2, MMP-9, and eNOS (89–91,97). All these results demonstrate that targeting NF-κB signaling by nutraceuticals could enhance the anti-cancer effects of conventional therapies for the treatment of pancreatic cancer; however, proof-of-concept and therapeutic clinical trials must be done to validate the importance of nutraceuticals in the treatment design for pancreas cancer.…”