Xiwei Ding

Nonsteroidal anti-inflammatory drugs for prevention of post-ERCP pancreatitis: a meta-analysis

BACKGROUND The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of post-ERCP pancreatitis (PEP) is still controversial. OBJECTIVE We performed a meta-analysis to evaluate the efficacy and safety of NSAIDs for PEP prophylaxis. DESIGN We systematically searched PubMed, EMBASE, Web of Science, and the Cochrane Library for relevant studies published updated to June 2012. SETTING Meta-analysis. PATIENTS Patients undergoing ERCP. INTERVENTIONS NSAIDs use for the prevention of PEP. MAIN OUTCOME MEASUREMENTS Overall incidence of PEP, incidence of moderate to severe PEP, and adverse events. RESULTS Ten RCTs involving 2269 patients were included. Meta-analysis showed that NSAID use decreased the overall incidence of PEP (risk ratio [RR], 0.57; 95% CI, 0.38-0.86; P = .007). The absolute risk reduction was 5.9%. The number needed to treat was 17. Heterogeneity among the studies was substantial. However, after removing the main source of heterogeneity, the prophylactic efficacy was similar (RR, 0.53; 95% CI, 0.41-0.68; P < .001). NSAID use also decreased the incidence of moderate to severe PEP (RR 0.46; 95% CI, 0.28-0.75; P = .002). The absolute risk reduction was 3.0%. The number needed to treat was 34. No differences of the adverse events attributable to NSAIDs were observed. LIMITATIONS Inclusion of low-quality studies, different type and route of administration of the NSAIDs, study heterogeneity, inconsistent use of pancreatic stenting. CONCLUSIONS Prophylactic use of NSAIDs reduces the incidence and severity of PEP.

Proton pump inhibitor selectively suppresses proliferation and restores the chemosensitivity of gastric cancer cells by inhibiting STAT3 signaling pathway

BACKGROUNDS AND AIMS Recent studies reported that pretreatment of proton pump inhibitors (PPIs) induced sensitization to chemotherapeutic agents in several cancer cells. The devastating effects of PPIs on tumor cells were discovered and raised great interests; therefore we designed the following experiments to fully explain the direct antitumor effects of PPIs. METHODS We compared the viability of gastric cancer cells and epithelia cells in buffered and unbuffered culture conditions with PPZ treatment by WST-8 assay. The sensitivity to cisplatin of gastric cancer cells with/without PPZ pretreatment was assessed by IC50 calculation and Annexin V/PI assay. The secretion of IL-6 was detected by ELISA. Western blot analysis and real time RT-PCR were used to evaluate the expression and activation of STAT3 and its downstream targets. RESULTS PPZ selectively exhibited a dose-dependent cytotoxic effect of gastric cancer cells in acidic unbuffered medium. Low dose of PPZ pretreatment (20 μg/mL) enhanced the sensitivity to cisplatin in gastric cancer cells. PPZ induced cell apoptosis and reduced the secretion of the pro-inflammatory cytokine IL-6 specifically in gastric cancer cells, but had no effect on the epithelia cells. Consequently, the activation of STAT3, not the total amount, was suppressed by PPZ in gastric cancer cells. The downstream targets of STAT3, c-Myc, cyclin D1 and Bcl-2 were also down-regulated. CONCLUSION PPZ causes gastric cancer cell death by induction of apoptosis and its mechanism of action is mediated in part via the inhibition of IL-6/STAT3 pathway.

Low nanomolar concentrations of Cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo

Cucurbitacin-I (Cu-I, also known as Elatericin B or JSI-124) is developed to inhibit constitutive and abnormal activation of STAT3 in many cancers, demonstrating a potent anticancer activity by targeting disruption of STAT3 function. Here, we for the first time systematically studied the underlying molecular mechanisms of Cu-I-induced gastric cancer cell death both in vitro and in vivo. In our study, we show that Cu-I markedly inhibits gastric cancer cell growth by inducing G2/M phase cell cycle arrest and apoptosis at low nanomolar concentrations via a STAT3-independent mechanism. Notably, Cu-I significantly decreases intracellular GSH/GSSG ratio by inhibiting NRF2 pathway to break cellular redox homeostasis, and subsequently induces the expression of GADD45α in a p53-independent manner, and activates JNK/p38 MAPK signaling. Interestingly, Cu-I-induced GADD45α and JNK/p38 MAPK signaling form a positive feedback loop and can be reciprocally regulated by each other. Therefore, the present study provides new insights into the mechanisms of antitumor effects of Cu-I, supporting Cu-I as an attractive therapeutic drug in gastric cancer by modulating the redox balance.

Gemcitabine-treated pancreatic cancer cell medium induces the specific CTL antitumor activity by stimulating the maturation of dendritic cells ☆

Gemcitabine (GEM) is a first line chemotherapeutic drug for advanced pancreatic cancer. Dendritic cell (DC) vaccine is a promising method of immunotherapy for malignant tumor. Recent research has indicated that gemcitabine can enhance the efficacy of DC vaccine, but precise mechanism is still unknown. Here, we aimed to investigate the effect of GEM on DCs. The results showed that GEM-treated pancreatic cancer cell medium stimulated maturation of DCs. When co-cultured with autologous T lymphocytes, the pulsed DCs promoted the proliferation of T cells, and exhibited specific cytotoxic T lymphocytes (CTLs) antitumor activity. Further research showed that stimulation of DC maturation may be related to the elevated level of Hsp70 induced by GEM. Our study indicates that GEM changes the immunogenicity of tumor cells, and enhances the efficacy of DC based immunotherapy for pancreatic cancer.

Downregulation of FOXP3 inhibits invasion and immune escape in cholangiocarcinoma

FOXP3 is known as a master control of regulatory T cells with recently studies indicating its expression in several tumor cells. In order to study the precise role of FOXP3 in cholangiocarcinoma, FOXP3 was knocked down in cholangiocarcinoma cell lines. Down regulation of FOXP3 inhibits tumor cell invasion by reducing the quantity of MMP-9 and MMP-2. With FOXP3 knocking down, IL-10 and TGF-β1 secreted by cancer cells diminishes and the cell survival of T cells is significant up-regulation. These results suggest that FOXP3 plays an important role in tumor malignant phenotype, especially the invasion and immune escape.

Efficacy and safety of endoscopic submucosal dissection for elderly patients with superficial squamous esophageal neoplasms

Background Little is known about the outcomes of endoscopic submucosal dissection in elderly patients with superficial squamous esophageal neoplasms. Objective To assess the efficacy and safety of endoscopic submucosal dissection for superficial squamous esophageal neoplasms in elderly patients (≥65 years) compared with non-elderly patients. Methods All patients with superficial squamous esophageal neoplasms receiving endoscopic submucosal dissection were retrospectively analyzed. Among them, 130 were aged 65 or older (group A), and 201 were aged younger than 65 years (group B). Therapeutic efficacy, adverse events, and follow-up data were evaluated. Results Group A had a higher prevalence of concomitant diseases than group B (52.3% vs. 14.9%, respectively). R0 resection rate was 82.3% in group A and 84.6 % in group B (P = 0.717). The curative resection rate was 80.8% in group A and 83.6% in group B (P = 0.653). The rate of procedure-related non-cardiopulmonary adverse events was 20.8% in group A and 16.9% in group B (P = 0.377). The incidence of cardiopulmonary adverse events during or after the procedure was 6.2% in group A and 2.5% in group B (P = 0.094). No procedure-related mortality was reported in either group. Conclusion Endoscopic submucosal dissection is effective and safe for treating superficial squamous esophageal neoplasms in elderly patients.

The Effects of HSP27 on Gemcitabine-Resistant Pancreatic Cancer Cell Line Through Snail.

Objectives To evaluate the regulation mechanism of heat shock protein 27 (HSP27) on gemcitabine (GEM) resistance of pancreatic cancer cell. Methods The expression vectors pEGFP-C1-HSP27 and the vectors of MicroRNA targeting Snail were introduced into GEM-sensitive pancreatic cancer SW1990 cells, and the vectors of small hairpin RNA targeting HSP27 were transfected into SW1990 and GEM-resistant SW1990/GEM cells. The expressions of HSP27, p-HSP27 (Ser82), Snail, ERCC1, and E-cadherin were evaluated by Western blotting. The sensitivity of transfected cells to GEM was detected by CCK-8 assay and Annexin V-FITC apoptosis assay. Results As compared to SW1990, SW1990/GEM showed significantly increased expressions of HSP27, p-HSP27, Snail and ERCC1 with decreased expression of E-cadherin. By increasing HSP27 expression, we found increase of Snail and ERCC1 with reduction of E-cadherin expressions, while reduction of HSP27 expression caused reduction of Snail and ERCC1 but increase of E-cadherin expressions. Downregulation of Snail resulted in the reduction of ERCC1 expression and increase of E-cadherin. Furthermore, downregulation of HSP27 or snail caused increased GEM sensitivity of pancreatic cancer cells, and upregulation of HSP27 showed the opposite results. Conclusions There is an inverse correlation between HSP27 expression and GEM sensitivity of SW1990 cells, which might be realized by regulating E-cadherin and ERCC1 expressions through Snail.

Gemcitabine sensitizes pancreatic cancer cells to the CTLs antitumor response induced by BCG-stimulated dendritic cells via a Fas-dependent pathway.

BACKGROUND/OBJECTIVES There are increasing evidences suggesting that chemotherapeutic agents can enhance the cytotoxic T lymphocytes (CTLs) antitumor effect, but the precise mechanism is not fully explained. This study aims to investigate whether gemcitabine (GEM) can sensitize pancreatic cancer cells to the CTLs antitumor response, and explore the potential mechanism. METHODS Cell counting kit-8 assays (CCK-8) were performed to determine the tumor cell proliferation. Flow cytometric analysis was conducted to analyze maturation of DCs and the expression of Fas. An Annexin V FITC Apoptosis Detection Kit was performed to detect tumor cell apoptosis. CytoTox 96 Nonradioactive Cytotoxicity assays were used to determine T cell-mediated tumor cell lysis. RESULTS First, it was demonstrated that Bacillus Calmette Guérin (BCG) could be used to induce effective CTLs antitumor response. Then, GEM inhibited the growth of SW1990 cells, induced apoptosis and upregulated the Fas expression even at a low concentration. When antagonistic anti-Fas mAb ZB4 was preincubated with GEM-treated SW1990 cells, the lysis induced by CTLs was reduced. Moreover, agonistic anti-Fas mAb CH11 induced more apoptosis of GEM-treated SW1990 cells. CONCLUSION Our results show that GEM sensitizes pancreatic cancer cells to the CTLs antitumor response, and the sensitization is associated with upregulation of Fas on pancreatic cancer cells.

The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses

Proton pump inhibitors (PPIs) play a role in antitumor activity, with studies showing specialized impacts of PPIs on cancer cell apoptosis, metastasis, and autophagy. In this study, we demonstrated that pantoprazole (PPI) increased autophagosomes formation and affected autophagic flux depending on the pH conditions. PPI specifically elevated SQSTM1 protein levels by increasing SQSTM1 transcription via NFE2L2 activation independent of the specific effect of PPI on autophagic flux. Via decreasing proteasome subunits expression, PPI significantly impaired the function of the proteasome, accompanied by the accumulation of undegraded poly-ubiquitinated proteins. Notably, PPI-induced autophagy functioned as a downstream response of proteasome inhibition by PPI, while suppressing protein synthesis abrogated autophagy. Blocking autophagic flux in neutral pH condition or further impairing proteasome function with proteasome inhibitors, significantly aggravated PPI cytotoxicity by worsening protein degradation ability. Interestingly, under conditions of mitochondrial stress, PPI showed significant synergism when combined with Bcl-2 inhibitors. Taken together, these findings provide a new understanding of the impact of PPIs on cancer cells’ biological processes and highlight the potential to develop more efficient and effective combination therapies.