Sepsis is a life-threatening condition that may develop to multiple organ failure and septic shock. Autophagy is considered to play an important role in the regulation of inflammation. The present study aims to investigate the protective role of mTORC1 inhibitor, rapamycin, on septic death using cecal ligation and puncture (CLP) mice model. Here, results showed that pretreatment with rapamycin reduced the pyroptosis of peritoneal macrophages stimulated by cecal contents and the release of inflammatory factors such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α); In septic mice, rapamycin treatment decreased the activation of inflammasome in lung, and alleviated the pathological injuries in lung, liver and spleen tissues during acute stage of sepsis. Treatment of rapamycin rescued animals from septic death significantly. Our results indicated that activation of autophagy is a potential strategy to regulate the excessive inflammation in acute stage of sepsis.

Purpose: Gastric and colon cancers have been the leading causes of cancer mortality in the world with limited therapy. Small molecules binding to bromodomains of bromodomain-containing protein 4 (BRD4) exert strong antitumor activities against hematological malignancies, while generally have limited efficacy in advanced solid tumors. Here, we found that the bromodomain and extra-terminal (BET)-bromodomain inhibitor JQ1, when combined with arsenic sulfide (As4S4, abbreviated as AS), synergistically decreased the expression of nuclear factor of activated T-cells (NFATs) as well as the downstream oncogene c-Myc and largely induced cell apoptosis via mitochondrial pathway in gastric and colon cancer cell lines. Methods: The synergistic cytotoxicity of AS and JQ1 in gastric and colon cancer cells was determined by MTT assay and verified by FACS assay. Western blot analysis and quantitative real-time PCR (qPCR) assay were used to detect the expression of NFATs and downstream apoptotic proteins. The mitochondrial transmembrane potential was determined by FACS assay, and the metastasis of cancer cells was detected by the wound-healing assay. Results: AS and JQ1 synergistically induced cell apoptosis in gastric and colon cancer cells by downregulating NFATs and upregulating apoptotic proteins. Combination of AS and JQ1 was associated with the decreased mitochondrial transmembrane potential, the cytochrome c release, and the subsequent caspase-3 activation. Conclusion: Thus, our data indicate that AS can effectively enhance the cytotoxicity of BET inhibitors in gastric and colon cancer cells through mitochondrial-mediated apoptosis induction.

Arsenic sulfide (As4S4) is the main component of Realgar which is widely used in traditional Chinese medicine. Previously we showed that As4S4 inhibited the proliferation of colon cancer cells through regulating nuclear factor of activated T cells (NFAT) pathway. Here we explore the role of NFAT in gastric cancer. We showed that As4S4 inhibited the expression of NFATc1, NFATc3, and NFATc4, and modulated the expression of NFATc2 accompanying with p53. The baseline expression of NFATc3 varied distinctly in gastric cancer cell lines (AGS, MGC803, MKN28, MKN45, and SGC7901) and the sensitivity of these cells to As4S4 was dissimilar, with AGS and MGC803 cells showing higher sensitivity while the SGC7901 cells relatively resistant. Interestingly, the sensitivity to As4S4 was correlated with the level of expression of NFATc3, and the cells relatively sensitivity just showing higher expression of NFATc3. Furthermore, NFATc3 expression was significantly higher in gastric cancer tissues compared with the adjacent normal tissues. Our data also showed that, NFATc3 promoted the proliferation of gastric cancer cells by regulating c-Myc. In conclusion, As4S4 inhibited the proliferation of gastric cancer cells through NFATc3/c-Myc pathway and the diverse sensitivity among different cell lines correlated with the expression level of NFATc3 indicating that NFATc3 may be a potential therapeutic target in gastric cancer.

肿瘤免疫治疗很早就被提出,也成为继肿瘤传统治疗方法 (化学治疗、手术治疗及放射治疗)之后的第四种肿瘤治疗方式.这种方法 的出现曾给肿瘤患者带来希望,但免疫治疗的进展并不突出.近几年,随着肿瘤学与免疫学的发展,免疫治疗逐渐发挥更加重要的作用,同时免疫学也拓展了人们对肿瘤的新视野,使得以前以肿瘤细胞为中心的观点发展为对肿瘤生物学行为复杂的、整体的认知.肿瘤免疫治疗方法 主要有以T细胞为主的治疗、肿瘤疫苗治疗及以抗体为主的治疗.本文主要介绍肿瘤免疫治疗新进展以及面临的挑战.

溴结构域蛋白4，是一种在哺乳动物细胞中广泛表达的染色质“适配器”，可以在整个有丝分裂过程中始终结合到染色体上，募集不同的染色质修饰蛋白，广泛调控基因的表达，从而在调控细胞周期进程、转录、炎症等方面发挥重要作用。近年来，很多学者对溴结构域蛋白4进行了深入系统的研究，发现其表达水平失调或功能紊乱与多种肿瘤的发生、发展密切相关。并且，溴结构域蛋白4的 shRNA 及超末端结构家族抑制剂显示出强大的抗肿瘤活性，有望成为治疗肿瘤的新靶点，为治疗肿瘤提供了新的思路。

Background We previously showed that arsenic sulfide (As4S4) induced cell cycle arrest and apoptosis in several human solid tumor cell lines, including those of gastric cancer. In this study, we investigated the effect of As4S4 on the migration and invasion of gastric cancer cells both in vitro and in vivo. Methods The human gastric cancer cell lines AGS and MGC803 were selected as in vitro models. Wound-healing migration assay and Transwell invasion assay were carried out to determine the effects of As4S4 on cell migration and invasion. The expressions of E-cadherin, β-catenin, Sp1, KLF4, and VEGF were measured by Western blotting analysis. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 in MGC803 cells were demonstrated by zymography assay. A mouse xenograft model was established by inoculation with MGC803 cells, then intraperitoneal injected with As4S4 for 3 weeks and monitored for body weight and tumor changes. Finally, the inhibition rate of tumor growth was calculated, and the expression of proteins and genes associated with tumor invasion and metastasis in tumor tissues were measured by immunohistochemistry, Western blotting, and real-time polymerase chain reaction assay. Results As4S4 significantly inhibited the migration and invasion of gastric cancer cell lines. The expression of E-cadherin and KLF4 was upregulated, while the expressions of β-catenin, VEGF, and Sp1 were downregulated following treatment with As4S4. Moreover, the protease activities of MMP-2 and MMP-9 were suppressed by As4S4 in MGC803 cells. Meanwhile, As4S4 effectively suppressed the abilities of tumor growth and invasion in the xenograft tumor model. We found that As4S4 upregulated the expression of E-cadherin and downregulated the expression of β-catenin, Sp1, VEGF, and CD34 in mouse tumor tissues, consistent with the results in vitro. Conclusion As4S4 inhibited the migration and invasion of gastric cancer cells by blocking tumor cell adhesion, decreasing the ability of tumor cells to destroy the basement membrane, and therefore suppressing their angiogenesis.

Arsenic sulfide (As4S4) is the main component of realgar, which is widely used in traditional Chinese medicine. Previous studies have shown the beneficial effects of As4S4 in the treatment of hematological malignant diseases, however, its effects on solid tumors have yet to be fully elucidated. The current study aimed to explore the anti‑cancer effect and the mechanism of As4S4 on solid tumors in vitro and in vivo. Cells from four human solid tumor cell lines, including the MKN45 gastric cancer cell line, the A375 malignant melanoma cell line, the 8898 pancreatic carcinoma cell line and the HepG2 hepatocellular carcinoma cell line, were treated with As4S4 in vitro, using the L02 embryonic liver cells as a control. The efficacy of As4S4 was assessed in vivo using mice implanted with Lewis lung carcinoma cells. The results of the current study demonstrated that As4S4 significantly inhibited the proliferation of solid tumor cells in a dose‑ and time‑dependent manner, but produced a less pronounced effect on L02 cells. Additionally, As4S4 was observed to induce apoptosis (including morphological changes and an enhanced sub‑G1 population), which was accompanied by the activation of caspase‑3 and ‑9. Furthermore, treatment with As4S4 significantly inhibited the growth of implanted tumors in mice. These results suggest that As4S4 possesses potent in vitro and in vivo antitumor activity via the induction of cell apoptosis.

BACKGROUND:Arsenic compounds have modest cytotoxic activity in solid tumors. We investigated if arsenic sulfide (As4S4) in combination with other distinct agents could enhance its cytotoxic activity.METHODS:We used gastric and colon cancer cell lines to study the synergistic effect of As4S4 in combination with BRD4 inhibitor JQ1, or with chemotherapy drug cisplatin and irinotecan or with COX2 inhibitor celecoxib. We investigated the mechanism of the cytotoxic effect of these novel combinations.RESULTS:We found that when As4S4 was combined with JQ1, cisplatin, irinotecan or celecoxib, its cytotoxic activity was dramatically enhanced in both gastric and colon cancer cell lines. As4S4 and JQ1 inhibited BRD4 and c-Myc while activating p53 expression synergistically. As4S4 inhibited COX2 and cyclin D1 expression. When As4S4 was combined with chemotherapy drug cisplatin or COX2 inhibitor celecoxib, its inhibition of COX2, BCL2, and p38 expression was enhanced. As4S4 and cisplatin synergistically stimulated p53, phosphor-p38 (p-p38), and increased cleaved caspase 3 (c-caspase 3).CONCLUSION:As4S4 in combination with JQ1, cisplatin, irinotecan or celecoxib showed enhanced cytotoxic effect on gastric and colon cancer cells, indicating the potential application of these novel drug combinations as part of treatment strategy that warrants further investigation. As4S4 and JQ1 demonstrate synergistic activation of p53 and inhibition of c-Myc. As4S4 and cisplatin and celecoxib activated multiple apoptosis pathways.

目的:研究冬凌草甲素(ORI)对人结肠癌细胞株HCT116生长的影响及其可能机制.方法:以体外培养的HCT116细胞为研究对象,给予不同浓度(0、2.5、5、10、20 μ M)ORI处理HCT116细胞不同时间(0、24、48、72h),通过MTT法检测其对HCT116细胞增殖的影响,DAPI染色观察其对细胞核的形态的影响,western blot检测细胞内β-catenin、c-myc蛋白表达的变化.结果:①ORI可显著抑制HCT116细胞的增殖,且此作用随着浓度和作用时间的增加或延长而增强(P＜0.05).②ORI处理HCT116细胞24小时后,细胞核固缩的百分率随药物作用浓度的增加而增加.③5、10、20μM ORI处理HCT116细胞24小时后,细胞内的β-catenin、c-myc蛋白水平均显著下调,且随着ORI浓度的增加逐渐减少.结论:ORI能以浓度和时间依赖性的方式抑制HCT116细胞的增殖,其机制可能与Wnt/β-catenin信号通路有关.

Angiogenesis is an integral process in carcinogenesis, and molecular inhibitors of angiogenic factors are currently being tested as treatments for cancer. Sunitinib is an oral multitargeted tyrosine-kinase inhibitor that blocks activation through the stem cell-factor receptor (Kit) and platelet-derived growth-factor receptor. Sunitinib has shown potent antitumor activity against several solid tumors, including renal cell carcinoma, gastrointestinal stromal tumors, and neuroendocrine tumors in several Phase II/III trials. Recently, sunitinib has been used to treat other solid cancers, such as lung cancer, pancreatic cancer, chondrosarcoma, esophageal cancer, bladder cancer, glioma, and aggressive fibromatosis, and also showed potential efficacy in progression-free survival and overall survival. In this review, we examine the efficacy of sunitinib as a molecular-targeted therapy in patients with different types of solid cancers.

Abstract Background: Realgar, a Chinese traditional medicine, of which the main component is arsenic sulfide (As4A4), has potentially anti-tumor property in various cancers. We aimed to study the antitumor effect of Realgar in combination with chemotherapy drugs on human gastric cancer cells. Methods: Human gastric cancer AGS cells were treated with Realgar in combination with Oxaliplatin, Irinotecan, Cisplatin, 5-FU and docetaxol with escalating dose level. Antitumor effect was measured by 24,48-hr growth inhibition by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell morphology was observed under microscope. Results: Realgar in combination with chemotherapy drugs exhibited a dose-dependent and time-dependent cytotoxic effect on AGS cells. The combination of Realgar and Irinotecan or Cisplatin showed the most potent synergistic effect. Conclusions: Realgar combined with chemotherapy drugs such as Irinotecan or Cisplatin has potent antitumor effect on human gastric cancer cells. Further mechanistic and animal studies are being performed. Citation Format: Lian Zhang, Sungkyoung Kim, Wenping Ding, Leizhen Zheng, Li Zhang, Yingying Tong, Siyu Chen. Antitumor effect of Realgar in combination with chemotherapy drugs on human gastric cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5525. doi:10.1158/1538-7445.AM2014-5525

Background: Arsenic sulfide (As4S4), the main component of realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types, especially for acute promyelocytic leukemia. In this study, we aimed to explore the efficacy and mechanism of As4S4 in gastric cancer.Methods: The effect of As4S4 on cell proliferation and apoptosis of gastric cancer cells was investigated by MTT assay, 4', 6-diamidino-2-phenylindole (DAPI) staining, and annexin V-fluorescein isothiocyanate/propidium iodide staining using gastric cancer cell lines AGS (harboring wild-type p53) and MGC803 (harboring mutant p53) in vitro. The expression of apoptosis-related proteins was measured by Western blotting, real-time polymerase chain reaction, and immunohistochemistry analysis. Mouse xenograft models were established by inoculation with MGC803 cells, and the morphology and the proportion of apoptotic cells in tumor tissues were detected by hematoxylin and eosin staining and TdT-mediated dUTP nick end labeling (TUNEL) assay, respectively.Results: As4S4 inhibited the proliferation and induced apoptosis of AGS and MGC803 cells in a time- and dose-dependent manner. As4S4 upregulated the expression of Bax and MDM2 while downregulated the expression of Bcl-2. The expression of p53 increased significantly in the AGS cells but did not readily increase in the MGC803 cells, which harbored mutant p53. Pifithrin-alpha, a p53 inhibitor, blocked the modulation of As4S4 on AGS cells, but not on MGC803 cells. Using xenograft as a model, we showed that As4S4 suppressed tumor growth and induced apoptosis in vivo and that the expression of p53 increased accordingly.Conclusion: As4S4 is a potent cytotoxic agent for gastric cancer cells, as it induced apoptosis both in vitro and in vivo through a p53-dependent pathway. Our data indicate that As4S4 may have therapeutic potential in gastric cancer.

Objective:To investigate the role of realgar(As4S4) on regulating migration ability of HCT116 cells in vitro.Methods:The cytotoxicity effect of As4S4 on HCT116 cells was observed by MTT assay.The effect of As4S4 on migration ability was observed by cell migration test.Expression of E-cadherin,P53 and Notch1 protein and mRNA levels was determined by western blot assay and Real-time PCR assay.Results:The proliferation of HCT116 cells was inhibited by As4S4 in a dose-dependent manner.1 μM As4S4 showed no significant proliferation inhibition effect on HCT116 cells.With this dose,As4S4 reduced the migration ability of HCT116 cells by 52.00%±7.55%.As4S4 treatment up-regulated the protein and mRNA levels of E-cadherin,up-regulated the protein level of P53,but showed no effect on Notch1.Conclusion:As4S4 reduced the proliferation and migration ability of HCT116 cells.Inhibition of the migra-tion ability probably caused by the up-regulation of P53 and E-cadherin.

Objective: To investigate the effect of Arsenic Sulfide(As4 S4) on human acute T-cell leukemia cell line Jurkat and its mechanism.Methods: Jurkat cells were treated with Arsenic Sulfide in various concentrations(0,2.5,5,10,20 μM) for different durations(24,48 and 72 h).The inhibitive effect of Arsenic Sulfide on growth was detected by MTT method.The morphological changes and number of cells incubated with Arsenic Sulfide(0,5,10,20 μM) for 24 hours were observed under the inverted microscope.The expression of Cleaved Notch1 protein and C-myc protein was assayed by western blot after Jurkat cells were treated with Arsenic Sulfide in various concentrations(0,5,10 μM) for 24 hours.Results: ①The results of MTT showed Jurkat cell proliferation was inhibited in a time and concentration dependent manner after treatment of Arsenic Sulfide(P0.05).②As the drug concentration increased,the number of cells decreased while cell fragments increased.③Western blot assay indicated the expression of Cleaved Notch1 protein and C-myc protein reduced in Jurkat cells treated with Arsenic Sulfide for 24 hours.Conclusion: Arsenic Sulfide could inhibit Jurkat cell proliferation and the mechanism may be involved in Notch pathway.

Objective To evaluate the efficacy and safety profile of combining vandetanib with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Methods MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts, ESMO Abstracts, Wanfang Database, CNKI were searched. Eligible studies were the randomized clinical trials (RCTs) that compared the efficacy and safety profile of adding vandetanib to chemotherapy with single chemotherapy in patients with advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. All meta-analysis were performed using Review Manager 5.1. The fixed-effect model weighted by the Mantel-Haenszel method was used. When considerable heterogeneity was found (p<0.1, or I2>50%), further analysis (subgroup analysis, sensitivity analysis or random-effect model) was performed to identify potential cause. Results Results reported from 5 RCTs involving 2284 patients were included in the analysis. Compared to chemotherapy alone, the addition of vandetanib resulted in a significant longer PFS (HR 0.79 [0.72–0.87], p<0.00001) and a higher ORR (RR 1.75 [1.43–2.15], p<0.00001), but failed to show advantage on OS (HR 0.96 [0.87–1.06], p = 0.44). Conclusion Vandetanib has activity in NSCLC. Identification of predictive biomarkers is warranted in future trials to select a subset of patients with advanced NSCLC who may benefit from vandetanib.