Shuling Huang

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.

Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells.

Multidrug resistance is a major obstacle in the treatment of gastric cancer. The underlying mechanisms of this phenomenon have not been well understood. Accumulating evidence indicates that Stat3 plays an important role in tumorigenesis of various primary cancers and cancer cell lines by upregulating cell survival proteins and downregulating tumor suppressors. We propose that the Stat3 pathway is also involved in acquired drug resistance of gastric cancer. To test this hypothesis, we investigated the expression and activation of Stat3 in drug resistant gastric cancer cell lines. Western blotting and real-time reverse transcription-PCR determined that Stat3 and its target genes were overactivated and/or overexpressed in drug resistant cells. Inhibition of Stat3 function resulted in significant decreases in cisplatin resistance and enhanced apoptosis in drug resistant cells. The levels of Stat3 target oncogenes such as Bcl-2 and c-Myc were decreased with DPP, a Stat3 inhibitor, treatment, while the expression of tumor suppressor p53 was increased. Interestingly, the vacuolar ATPase, a proton pump which interferes the uptake of therapeutic drugs, was down regulated by Stat3 inhibition. In conclusion, these data supported the hypothesis that interruption of Stat3 signaling could reverse resistance to chemotherapy agents in human gastric cancer cells.

Reversal Effects of Pantoprazole on Multidrug Resistance in Human Gastric Adenocarcinoma Cells by Down-Regulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1 Signaling Pathway In Vitro and In Vivo

To investigate reversal effects of pantoprazole (PPZ) on multidrug resistance (MDR) in human gastric adenocarcinoma cells in vivo and in vitro. Human gastric adenocarcinoma cell SGC7901 was cultured in RPMI‐1640 medium supplemented with 10% fetal bovine serum and antibiotics in a humidified 5% CO2 atmosphere at 37°C. Adriamycin (ADR)‐resistant cells were cultured with addition of 0.8 µg/ml of ADR maintaining MDR phenotype. ADR was used to calculate ADR releasing index; CCK‐8 Assay was performed to evaluate the cytotoxicity of anti‐tumor drugs; BCECF‐AM pH‐sensitive fluorescent probe was used to measure intracellular pH (pHi) value of cells, whereas pH value of medium was considered as extracellular pH (pHe) value; Western blotting and immunofluorescent staining analyses were employed to determine protein expressions and intracellular distributions of vacuolar H+‐ATPases (V‐ATPases), mTOR, HIF‐1α, P‐glycoprotein (P‐gp), and multidrug resistant protein 1 (MRP1); SGC7901 and SGC7901/ADR cells were inoculated in athymic nude mice. Thereafter, effects of ADR with or without PPZ pretreatment were compared by determining the tumor size and weight, apoptotic cells in tumor tissues were detected by TUNEL assay. At concentrations greater than 20 µg/ml, PPZ pretreatment reduced ADR releasing index and significantly enhanced intracellular ADR concentration of SGC7901 (P < 0.01). Similarly, PPZ pretreatment significantly decreased ADR releasing index of SGC7901/ADR dose‐dependently (P < 0.01). PPZ pretreatment also decreased cell viabilities of SGG7901 and SGC7901/ADR dose‐dependently. After 24‐h PPZ pretreatment, administration of chemotherapeutic agents demonstrated maximal cytotoxic effects on SGC7901 and SGC7901/ADR cells (P < 0.05). The resistance index in PPZ pretreatment group was significantly lower than that in non‐PPZ pretreatment group (3.71 vs. 14.80). PPZ at concentration >10 µg/ml significantly decreased pHi in SGC7901 and SGC7901/ADR cells and diminished or reversed transmembrane pH gradient (P < 0.05). PPZ pretreatment also significantly inhibited protein expressions of V‐ATPases, mTOR, HIF‐1α, P‐gp, and MRP1, and alter intracellular expressions in parent and ADR‐resistant cells (P < 0.05). In vivo experiments further confirmed that PPZ pretreatment could enhance anti‐tumor effects of ADR on xenografted tumor of nude mice and also improve the apoptotic index in xenografted tumor tissues. PPZ pretreatment enhances the cytotoxic effects of anti‐tumor drugs on SGC7901 and reverse MDR of SGC7901/ADR by downregulating the V‐ATPases/mTOR/HIF‐1α/P‐gp and MRP1 signaling pathway. J. Cell. Biochem. 113: 2474–2487, 2012.

Endoscopic submucosal dissection vs endoscopic mucosal resection for superficial esophageal cancer

AIM To investigate the effectiveness of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) in treating superficial esophageal cancer (SEC). METHODS Studies investigating the safety and efficacy of ESD and EMR for SEC were searched from the databases of Pubmed, Web of Science, EMBASE and the Cochrane Library. Primary end points included the en bloc resection rate and the curative resection rate. Secondary end points included operative time, rates of perforation, postoperative esophageal stricture, bleeding and local recurrence. The random-effect model and the fixed-effect model were used for statistical analysis. RESULTS Eight studies were identified and included in the meta-analysis. As shown by the pooled analysis, ESD had significantly higher en bloc and curative resection rates than EMR. Local recurrence rate in the ESD group was remarkably lower than that in the EMR group. However, operative time and perforation rate for ESD were significantly higher than those for EMR. As for the rate of postoperative esophageal stricture and procedure-related bleeding, no significant difference was found between the two techniques. CONCLUSION ESD seems superior to EMR in the treatment of SEC as evidenced by significantly higher en bloc and curative resection rates and by obviously lower local recurrence rate.

Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-β/β-catenin signaling and epithelial–mesenchymal transition

The effect of proton pump inhibitor (PPI) on cancer risk has received much attention recently. In this study, we investigated the mechanism underlying multidrug resistance and the effect of a PPI pantoprazole using an adriamycin-resistant gastric cancer cell model (SGC7901/ADR). Compared with the parental cell line, SGC7901/ADR cells showed reduced proliferation rate, but higher resistance to adriamycin under both anchorage-dependent and -independent conditions. Notably, SGC7901/ADR cells underwent epithelial to mesenchymal transition (EMT) and showed increased migrating and invading capabilities. At molecular level, SGC7901/ADR cells showed strong activation of Wnt/β-catenin signaling pathway compared with parental sensitive cells. Interestingly, we found that a PPI pantoprazole can effectively reverse the aggressiveness and EMT marker expression of SGC7901/ADR cells. Furthermore, pantoprazole treatment resulted in a profound reduction of both total and phosphorylated forms of Akt and GSK-3β, which in turn suppressed the adriamycin-induced Wnt/β-catenin signaling in SGC7901/ADR cells. Taken together, we demonstrate that the aggressive phenotype of adriamycin-resistant SGC7901/ADR cells is mediated by induction of EMT and activation of the canonical Wnt/β-catenin signaling pathway. And for the first time, we show that it is possible to suppress the invasiveness of SGC7901/ADR cells by pantoprazole which targets the EMT and Akt/GSK-3β/β-catenin signaling.

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.

Co-ordinated overexpression of SIRT1 and STAT3 is associated with poor survival outcome in gastric cancer patients.

In many gastric cancer patients, the disease is diagnosed in an advanced stage and therefore the mortality levels are high. Because there is a need to identify novel early diagnostic and prognostic biomarkers, we tested whether SIRT1 and STAT3 are good candidates. Towards this, we used patient tissues representing different stages of gastric cancer including gastric pre-cancerous lesions, early gastric cancer, and advanced gastric cancer, and probed SIRT1, STAT3 and phosphorylated STAT3 (pSTAT3) levels using immunohistochemistry. Our results revealed upregulated expression of SIRT1 in all stages of gastric cancer compared with noncancerous gastric mucosa, suggesting that high SIRT1 levels are likely involved in establishing gastric neoplasticity. However, STAT3 and pSTAT3 levels remained low until the gastric mucosa reached the tumor stage. Moreover, co-ordinated high expression of SIRT1 and STAT3 predicted poor overall survival for advanced gastric cancer patients. In addition, through analysis of gastric cancer patients from the TCGA dataset, we identified SIRT2 as an independent prognostic factor in gastric cancer patients. We postulate that SIRT1 and STAT3 are potential early diagnostic and prognostic markers of gastric cancer. Our study also shows that SIRT1 acts a gatekeeper during gastric tumorigenesis.

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.