Yu-Quan Wei

Publications of Yu-Quan Wei

• Vector-based miR-15a/16-1 plasmid inhibits colon cancer growth in vivo.

  Authors: Lixia Dai, Wei Wang, Shuang Zhang, Qingyuan Jiang, Ruibo Wang, Lei Dai, Lin Cheng, Yang Yang, Yu-Quan Wei, Hong-Xin Deng

  Cell biology international. 05/2012;

  miR-15 and miR-16 are frequently deleted or down-regulated in many cancer cell lines and various tumor tissues, suggesting that miR-15a/16-1 might play important roles in tumor progression and mightmiR-15 and miR-16 are frequently deleted or down-regulated in many cancer cell lines and various tumor tissues, suggesting that miR-15a/16-1 might play important roles in tumor progression and might be a method for cancer treatment. The purpose of this study was to develop a vector-based plasmid to explore the antitumor efficacy of miR-15a/16-1 in colon cancer in vivo. Here, we propose that miR-15a and miR-16-1 may target cyclin B1 (CCNB1) which associates with several tumorigenic features such as survival and proliferation. The levels of miR-15a and miR-16-1 in colon cancer cells are inversely correlated with CCNB1 expression, and we found consensus between miR-15a/16-1 and CCNB1 mRNA sequences by analyzing homology. In the present study, vector-based miR-15a/16-1 expression plasmid was constructed and transfected into HCT 116 and SW620 colon cancer cells in vitro. The negative effects produced on cell viability and angiogenesis were analyzed using flow cytometric analysis, colony formation analysis and tube formation analysis. CCNB1 expression down-regulated was certified by western blotting analysis. Systemic delivery of miR-15a/16-1 plasmids encapsulated in cationic liposome led to a significant inhibition of subcutaneous tumor growth and angiogenesis in tumor tissues, whereas no effects were observed with liposome carrying the non-specific plasmid. Summarily, it's the first time miR-15a/16-1 was applied into colon cancer treatment in vivo, and had resulted in colon tumor xenografts growth arrest and angiogenesis decrease effectively. These findings suggested that systemic delivery of vector-based miR-15a/16-1 expression plasmid might be a potential approach for human colon cancer therapy.

• Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat.

  Authors: Hui-Qiong Huang, Jing Tang, Sheng-Tao Zhou, Tao Yi, Hong-Ling Peng, Guo-Bo Shen, Na Xie, Kai Huang, Tao Yang, Jin-Hua Wu, Can-Hua Huang, Yu-Quan Wei, Xia Zhao

  International journal of oncology. 05/2012;

  Orlistat is an orally administered anti-obesity drug that has shown significant antitumor activity in a variety of tumor cells. To identify the proteins involved in its antitumor activity, weOrlistat is an orally administered anti-obesity drug that has shown significant antitumor activity in a variety of tumor cells. To identify the proteins involved in its antitumor activity, we employed a proteomic approach to reveal protein expression changes in the human ovarian cancer cell line SKOV3, following Orlistat treatment. Protein expression profiles were analyzed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification was performed on a MALDI-Q-TOF MS/MS instrument. More than 110 differentially expressed proteins were visualized by 2-DE and Coomassie brilliant blue staining. Furthermore, 71 proteins differentially expressed proteins were positively identified via mass spectrometry (MS)/MS analysis. In particular, PKM1/2, a key enzyme involved in tumorigenesis, was found to be significantly downregulated in SKOV3 cells following treatment with Orlistat. Moreover, PKM1/2 was proved to be downregulated in SKOV3 cells by western blot analysis after treatment with Orlistat. Taken together, using proteomic tools, we identified several differentially expressed proteins that underwent Orlistat-induced apoptosis, particularly PKM2. These changes confirmed our hypothesis that Orlistat is a potential inhibitor of ovarian cancer and can be used as a novel adjuvant antitumor agent.

• Cancer Microenvironment and Cancer Vaccine.

  Authors: Zhen-Yu Ding, Xue-Lin Zou, Yu-Quan Wei

  Cancer microenvironment : official journal of the International Cancer Microenvironment Society. 05/2012;

  The cancer microenvironment is constituted of non-transformed host stromal cells such as endothelial cells, fibroblasts, various immune cells, and a complex extra-cellular matrix secreted by both theThe cancer microenvironment is constituted of non-transformed host stromal cells such as endothelial cells, fibroblasts, various immune cells, and a complex extra-cellular matrix secreted by both the normal and neoplastic cells embedded in it. The importance of the microenvironment and its potential in cancer therapy is just being established. Among modalities that target the microenvironment, cancer vaccine is a unique strategy which is aimed to elicit specific immunity against components in the microenvironment. Most, if not all, components can be targeted by the vaccines. The most extensively studied are the endothelial cells, fibroblasts and macrophages as well as ECM. Vaccines are in development for each of them. All the vaccines were proved to be effective at providing protective or therapeutic anti-tumor effects in the pre-clinical models. A few of them have been tested in the clinical trials. The mechanisms of the vaccines were mainly related to the cellular immune response such as CD8+ cytotoxic T cells, and in some instances CD4+ Th cells were involved as well. The present review also discussed the hurdles associated with the microenvironment-based vaccines such as the selection of suitable patients with appropriate biomarkers. With the rapid increase of our knowledge in the cancer microenvironment, the proof-of-concept of microenvironment-based cancer vaccines will surely expand our armamentarium against cancer.

• Discovery of the Novel Potent and Selective FLT3 Inhibitor 1-{5-[7-(3- Morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and Its Anti-Acute Myeloid Leukemia (AML) Activities in vitro and in vivo.

  Authors: Wei-Wei Li, Xiao-Yang Wang, Ren-Lin Zheng, Heng-Xiu Yan, Zhi-Xing Cao, Lei Zhong, Ze-Rong Wang, Pan Ji, Ling-Ling Yang, Li-Jiao Wang, Yong Xu, Jing-Jing Liu, Jiao Yang, Chun-Hui Zhang, Shuang Ma, Shan Feng, Qi-Zheng Sun, Yu-Quan Wei, Sheng-Yong Yang

  Journal of medicinal chemistry. 03/2012;

  Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which is for optimizing the in vitro and in vivo anti-acute myeloid leukemia (AML) activity of aStructure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which is for optimizing the in vitro and in vivo anti-acute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, which results showed that 1-{5-[7-(3-Morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.

• In vitro and in vivo anti-tumor activities of anti-EGFR single-chain variable fragment fused with recombinant gelonin toxin.

  Authors: Xikun Zhou, Ji Qiu, Zhen Wang, Nongyu Huang, Xiaolei Li, Qian Li, Yinbing Zhang, Chengjian Zhao, Can Luo, Nannan Zhang, Xiu Teng, Zhongwen Chen, Xiao Liu, Xianlian Yu, Wenling Wu, Yu-Quan Wei, Jiong Li

  Journal of cancer research and clinical oncology. 03/2012;

  PURPOSE: Epidermal growth factor receptor (EGFR) plays an important role in the growth and metastasis of many solid tumors. Strategies that target EGFR hold promising therapeutic potential for thePURPOSE: Epidermal growth factor receptor (EGFR) plays an important role in the growth and metastasis of many solid tumors. Strategies that target EGFR hold promising therapeutic potential for the treatment for non-small cell lung cancer (NSCLC), as EGFR is normally overexpressed in these tumors. This study was designed to determine whether an anti-EGFR immunotoxin has anti-tumor activity against NSCLC, and if so, to further investigate the possible mechanisms of cytotoxicity. METHODS: A fusion protein of anti-EGFR single-chain variable fragment (anti-EGFR scFv) and the plant toxin gelonin (rGel) was constructed, expressed in bacteria, and purified to homogeneity. Cytotoxicity of anti-EGFR scFv/rGel (E/rG) immunotoxin was assessed on A549, HCC827, and H1975 cells (EGFR-overexpressing NSCLC-derived cell lines) and A549 xenografts in nude mice. RESULTS: Cytotoxicity experiments using E/rG on A549, HCC827, and H1975 cells demonstrated that E/rG can specifically inhibit proliferation of these cells, whereas it did not affect the proliferation of Raji cells that do not express EGFR. Treatment for A549 xenografts in nude mice with E/rG resulted in significant suppression of tumor growth compared to controls. Immunofluorescence in frozen tissue sections confirmed that E/rG could specifically bind to tumor tissues in nude mice bearing A549 tumor xenografts, while rGel alone showed no binding activity. Furthermore, E/rG inhibited the growth of A549 cells by cytotoxic effects that blocked tumor proliferation, and the immunotoxin-induced cell death may be mediated by autophagy. CONCLUSIONS: These results showed that E/rG might have significant potential as a novel clinical therapeutic agent against human NSCLC.

• (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione protects rats from carbon tetrachloride-induced liver injury and fibrogenesis.

  Authors: Zhi-Zhi Chen, Zheng-Lin Wang, Chong-Yang Deng, Hao Zheng, Xian-Huo Wang, Liang Ma, Xia Ye, Ying-Hua Ma, Cai-Feng Xie, Li-Juan Chen, Yu-Quan Wei

  World journal of gastroenterology : WJG. 02/2012; 18(7):654-61.

  To evaluate the hepatoprotective roles of (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (SKLB010) against carbon tetrachloride (CCl₄)-induced acute and chronic liver injury and its underlyingTo evaluate the hepatoprotective roles of (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (SKLB010) against carbon tetrachloride (CCl₄)-induced acute and chronic liver injury and its underlying mechanisms of action. In the first experiment, rats were weighed and randomly divided into 5 groups (five rats in each group) to assess the protective effect of SKLB010 on acute liver injury. For induction of acute injury, rats were administered a single intraperitoneal injection of 2 mL/kg of 50% (v/v) CCl₄ dissolved in olive oil (1:1). Group 1 was untreated and served as the control group; group 2 received CCl₄ for induction of liver injury and served as the model group. In groups 3, 4 and 5, rats receiving CCl₄ were also treated with SKLB010 at doses of 25, 50 and 100 mg/kg, respectively. Blood samples were collected at 6, 12 and 24 h after CCl₄ intoxication to determine the serum activity of alanine amino transferase. Tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) were determined using enzyme-linked immunosorbent assay. At 24 h after CCl₄ injection, liver fibrogenesis was evaluated by hematoxylin-eosin (HE) staining and immunohistochemical analyses. Cytokine transcript levels of TNF-α, IL-1β and inducible nitric oxide synthase in the liver tissues of rats were measured using a reverse transcriptase reverse transcription-polymerase chain reaction technique. In the second experiment, rats were randomly divided into 2 groups (15 rats in each group), and liver injury in the CCl₄-administered groups was induced by a single intraperitoneal injection of 2 mL/kg of 50% (v/v) CCl₄ dissolved in olive oil (1:1). The SKLB010-treated groups received oral 100 mg/kg SKLB010 before CCl₄ administration. Five rats in each group were sacrificed at 2 h, 6 h, 12 h after CCl₄ intoxication and small fortions of livers were rapidly frozen for extraction of total RNA, hepatic proteins and glutathione (GSH) assays. In the hepatic fibrosis model group, rats were randomly divided into 2 groups (5 rats each group). Rats were injected intraperitoneally with a mixture of CCl₄ (1 mL/kg body weight) and olive oil [1:1 (v/v)] twice a week for 4 wk. In the SKLB010-treated groups, SKLB010 (100 mg/kg) was given once daily by oral gavage for 4 wk after CCl₄ administration. The rats were sacrificed one week after the last injection and the livers from each group were harvested and fixed in 10% formalin for HE and immunohistochemical staining. In this rat acute liver injury model, oral administration of SKLB010 blocked liver tissue injury by down-regulating the serum levels of alanine aminotransferase, suppressing inflammatory infiltration to liver tissue, and improving the histological architecture of liver. SKLB010 inhibited the activation of NF-κB by suppressing the degradation of IκB, and prevented the secretion of pro-inflammatory mediators such as tumor necrosis factor-α, interleukin-1β, and the reactive free radical, nitric oxide, at the transcriptional and translational levels. In this chronic liver fibrosis model, treatment with 100 mg/kg per day SKLB010 attenuated the degree of hepatic fibrosis and area of collagen, and blocked the accumulation of smooth-muscle actin-expressed cells. These results suggest that SKLB010 is a potent therapeutic agent for the treatment of CCl₄-induced hepatic injury.

• SKLB1206, a novel orally available multi-kinase inhibitor targeting EGFR activating and T790M mutants, ErbB2, ErbB4 and VEGFR2, displays potent antitumor activity both in vitro and in vivo.

  Authors: Youli Pan, Yong Xu, Shan Feng, Shidong Luo, Renlin Zheng, Jiao Yang, Lijiao Wang, Lei Zhong, Hanyu Yang, Binglin Wang, Yang Yu, Jingjing Liu, Zhixing Cao, Xiaoyan Wang, Pan Ji, Zerong Wang, Xin Chen, Shuang Zhang, Yu-Quan Wei, Sheng-Yong Yang

  Molecular cancer therapeutics. 02/2012;

  Anti-epidermal growth factor receptor (EGFR) treatment has been successfully applied in clinical cancer therapy. However, the clinical efficacy of first-generation reversible EGFR inhibitors, such asAnti-epidermal growth factor receptor (EGFR) treatment has been successfully applied in clinical cancer therapy. However, the clinical efficacy of first-generation reversible EGFR inhibitors, such as gefitinib and erlotinib, is limited by the development of drug-resistant mutations, including the gatekeeper T790M mutation and upregulation of alternative signaling pathways. Second-generation irreversible EGFR inhibitors that were designed to overcome the drug resistance due to the T790M mutation have thus far had limited success. Here we report a novel reversible EGFR inhibitor, SKLB1206, which has potent activity against EGFR with gefitinib-sensitive and resistant (T790M) mutations. In addition, SKLB1206 has also considerable inhibition potency against some other related onco-kinases, including ErbB2, ErbB4 and vascular endothelial growth factor receptor 2 (VEGFR2). SKLB1206 exhibited highly anti-proliferative activity against a range of EGFR mutant cell lines, including gefitinib-sensitive and resistant cell lines, and EGFR or ErbB2-overexpressing cell lines. SKLB1206 also showed a potent anti-angiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 demonstrated complete tumor regression in gefitinib-sensitive HCC827 and PC-9 xenograft models, and showed a considerable antitumor effect on the gefitinib-resistant H1975 model as well as other EGFR/ErbB2-overexpressing or -dependent tumor models including A431, LoVo and N87 established in athymic mice. SKLB1206 also showed a very good oral bioavailability (50.1%). Collectively, these preclinical evaluations may support clinical development of SKLB1206 for cancers with EGFR activating/resistance mutations or EGFR/ErbB2 overexpressed.

• Novel gene hBiot2 is an independent prognostic factor in colorectal cancer patients.

  Authors: Yang-Mei Shen, Gunnar Arbman, Per Sandström, Per Gullstrand, Yu-Quan Wei, Hong Zhang, Johan Rosell, Birgit Olsson, Feng Peng, Han-Shuo Yang, Chun-Ting Wang, Xiao-Feng Sun

  Oncology reports. 02/2012; 27(2):376-82.

  The present study investigated the expression of the novel gene hBiot2 in colorectal cancer (CRC) and its relationships with clinicopathological variables in CRC patients. The expression of hBiot2 inThe present study investigated the expression of the novel gene hBiot2 in colorectal cancer (CRC) and its relationships with clinicopathological variables in CRC patients. The expression of hBiot2 in 163 primary CRCs together with the corresponding normal mucosa, 36 liver metastases and 5 colon cancer cell lines was examined using real-time PCR. In situ hybridization (ISH) was performed to evaluate the localization of hBiot2 expression in CRC and normal mucosa. hBiot2 expression at the RNA level was localized in the nucleus of tumor cells and normal epithelial cells. The mean expression of hBiot2 in the CRCs (243.571±564.569) was higher compared to the normal mucosa (107.252±413.635, P<0.0001) and liver metastasis samples (42.002±40.809, P=0.0002). hBiot2 expression was increased from stages I+II to III (P=0.047), and no difference in the expression was found in stages III and IV (P=0.452). A high value of hBiot2 was associated with a poorer prognosis compared with a low value independently of gender, age, tumor site, stage and differentiation (P=0.007, RR 7.519, 95% CI 1.729-32.704). Liver metastasis, smaller tumors, non-local recurrence and primary liver surgery alone were associated with a higher value of hBiot2 compared to larger tumors, local recurrence and repeated liver surgery (P=0.003, 0.044 and 0.026, respectively). An inverse relationship was found between hBiot2 expression and the metastatic potential of the colon cancer cell lines. Thus, increased expression of hBiot2 may be an early and interim event in the development of CRC. A higher expression of hBiot2 in primary CRC patients independently indicates a poorer prognosis.

• AAV-mediated gene transfer of human pigment epithelium-derived factor inhibits lewis lung carcinoma growth in mice.

  Authors: Sha-Sha He, Hua-Shan Shi, Tao Yin, Yong-Xia Li, Shun-Tao Luo, Qin-Jie Wu, Lian Lu, Yu-Quan Wei, Li Yang

  Oncology reports. 01/2012; 27(4):1142-8.

  Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, and mechanisms through which PEDF exerts its antitumour activity have recently beenPigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, and mechanisms through which PEDF exerts its antitumour activity have recently been defined. The aim of our research was to evaluate the ability of adeno-associated virus (AAV) vector-mediated transfer of human PEDF to inhibit lewis lung carcinoma (LCC) cell growth. Intratumoural injection of AAV-PEDF caused significant reduction of the tumour volume and prolonged the survival time of mice bearing LLC cells, which were associated with decreased microvessel density and increased apoptosis in the tumours. AAV vectors represent a very promising tool for cancer gene therapy. No noticeable toxicity concerning AAV was detected as inferred from monitoring changes in animal body weight as well as basic organ structure and histological morphology, and by analyzing mouse liver and kidney function. Our findings indicate that AAV-mediated PEDF gene expression may offer an active approach to inhibit LLC growth and that treatment with AAV-PEDF may provide a promising therapeutic strategy in lung cancer treatment.

• NOXA-Induced Alterations in the Bax/Smac Axis Enhance Sensitivity of Ovarian Cancer Cells to Cisplatin.

  Authors: Chao Lin, Xin-Yu Zhao, Lei Li, Huan-Yi Liu, Kang Cao, Yang Wan, Xin-Yu Liu, Chun-Lai Nie, Lei Liu, Ai-Ping Tong, Hong-Xin Deng, Jiong Li, Zhu Yuan, Yu-Quan Wei

  PloS one. 01/2012; 7(5):e36722.

  Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarianOvarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy.

• TP-58, a Novel Thienopyridine Derivative, Protects Mice from ConcanavalinA-Induced Hepatitis by Suppressing Inflammation.

  Authors: Yi Li, Zhen-Ling Wang, Fang He, Yang Wu, Wen Huang, Yang He, Qing-Yi Tong, Yu-Quan Wei, Yong Qing, Li Yang, Xiaohua Wu

  Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 01/2012; 29(1-2):31-40.

  Hepatitis represents a ubiquitous human health problem but effective therapies with limited side effects are still lacking. In this study, we investigated the effect and mechanism of TP-58, a novelHepatitis represents a ubiquitous human health problem but effective therapies with limited side effects are still lacking. In this study, we investigated the effect and mechanism of TP-58, a novel thienopyridine derivative, on a murine fulminant hepatitis model induced by concanavalin A (ConA). We found TP-58 markedly alleviated ConA-caused liver injury and increased survival ratio of mice injected with a lethal dose of ConA. Oral administration of TP-58 significantly alleviated ConA-caused liver injury in mice by the reduction of serum aminotransferases and liver necrosis.The analysis of proinflammatory cytokines showed that TP-58 decreased both hepatic mRNA expressions and serum protein levels of TNF-α and IL-6. And the result from LPS-stimulated RAW 264.7 cells showed TP-58 suppressed the production of TNF-α, IL-6, and Nitro Oxide (NO) in the supernatant of LPS-stimulated RAW 264.7 cells. The study of activation of nuclear factor-κB (NF-κB) by electrophoretic mobility shift assay (EMSA) showed that TP-58 inhibited the activation of NF-κB both in vivo and in vitro. The inhibitory effect was also accompanied by a parallel reduction of IκB phosphorylation. These results indicate that TP-58 protects against liver injury by inhibition of the NF-κB-mediated inflammation and suggest a potential role of TP-58 against acute liver injury and other inflammatory diseases.

• Synthesis and Biological Evaluation of Novel Benzothiazole-2-thiol Derivatives as Potential Anticancer Agents.

  Authors: Xuan-Hong Shi, Zhao Wang, Yong Xia, Ting-Hong Ye, Mei Deng, You-Zhi Xu, Yu-Quan Wei, Luo-Ting Yu

  Molecules (Basel, Switzerland). 01/2012; 17(4):3933-44.

  A series of novel benzothiazole-2-thiol derivatives were synthesized and their structures determined by 1H-NMR, 13C-NMR and HRMS (ESI). The effects of all compounds on a panel of different types ofA series of novel benzothiazole-2-thiol derivatives were synthesized and their structures determined by 1H-NMR, 13C-NMR and HRMS (ESI). The effects of all compounds on a panel of different types of human cancer cell lines were investigated. Among them, pyridinyl-2-amine linked benzothiazole-2-thiol compounds 7d, 7e, 7f and 7i exhibited potent and broad-spectrum inhibitory activities. Compound 7e displayed the most potent anticancer activity on SKRB-3 (IC(50) = 1.2 nM), SW620 (IC(50) = 4.3 nM), A549 (IC(50) = 44 nM) and HepG2 (IC(50) = 48 nM) and was found to induce apoptosis in HepG2 cancer cells.

• A novel vaccine delivery system: biodegradable nanoparticles in thermosensitive hydrogel.

  Authors: Qin Jie Wu, Xue Chen Zhu, Xiong Xiao, Pan Wang, Da Ke Xiong, Chang Yang Gong, Yong Sheng Wang, Li Yang, Yu Quan Wei

  Growth factors (Chur, Switzerland). 12/2011; 29(6):290-7.

  In this work, a novel vaccine delivery system, biodegradable nanoparticles (NPs) in thermosensitive hydrogel, was investigated. Human basic fibroblast growth factor (bFGF)-loaded NPs (bFGF-NPs) wereIn this work, a novel vaccine delivery system, biodegradable nanoparticles (NPs) in thermosensitive hydrogel, was investigated. Human basic fibroblast growth factor (bFGF)-loaded NPs (bFGF-NPs) were prepared, and then bFGF-NPs were incorporated into thermosensitive hydrogel to form bFGF-NPs in a hydrogel composite (bFGF-NPs/hydrogel). bFGF-NPs/hydrogel was an injectable sol at ambient temperature, but was converted into a non-flowing gel at body temperature. The in vitro release profile showed that bFGF could be released from bFGF-NPs or bFGF-NPs/hydrogel at an extended period, but the release rate of bFGF-NPs/hydrogel was much lower. In vivo experiments suggested that immunogenicity of bFGF improved significantly after being incorporated into the NPs/hydrogel composite, and strong humoral immunity was maintained for longer than 12 weeks. Furthermore, an in vivo protective anti-tumor immunity assay indicated that immunization with bFGF-NPs/hydrogel could induce significant suppression of the growth and metastases of tumors. Thus, the NPs/hydrogel composite may have great potential application as a novel vaccine delivery system.

• Hyperthermia increases the therapeutic efficacy of survivinT34A in mouse tumor models.

  Authors: Zhi-Mian Li, Yu-Wei Zhao, Cheng-Jian Zhao, Xiao-Ping Zhang, Li-Juan Chen, Yu-Quan Wei, Han-Shuo Yang

  Cancer biology & therapy. 09/2011; 12(6):523-30.

  The use of survivinT34A mutant targeted disruption of survivin, the strongest inhibitor of apoptosis protein overexpressed in tumors, has proved a promising strategy for advanced cancers. However,The use of survivinT34A mutant targeted disruption of survivin, the strongest inhibitor of apoptosis protein overexpressed in tumors, has proved a promising strategy for advanced cancers. However, hyperthermia, as a cytotoxic enhancer, regularly activates the expression of survivin to counteract the heat-induced antitumor activity. Here, we investigated the combinational antitumor effect by using liposome-encapsulated mouse survivinT34A and hyperthermia in mouse models. We observed that the combination treatment of surivinT34A and hyperthermia significantly increased the growth inhibition and apoptosis of tumor cells in vitro compared with single treatment or other controls, which was similar to the effect of survivin silencing in combination with hyperthermia. Moreover, the inhibition of tumor growth in vivo was also remarkably enhanced by combination of surivinT34A and hyperthermia when compared with other treatments. Naturally, the tumor tissues in combination treatment presented the larger necrosis-like areas, more apoptotic cells and less microvessel density. Our findings suggest that the antitumor efficacy of survivin disruption can be enhanced by hyperthermia, which might be a new feasible approach for cancer therapy.

• [The molecular mechanism of extravasation in mouse melanoma lung metastasis model].

  Authors: Lu-Ming Pang, Cheng-Jian Zhao, Yu-Wei Zhao, Zhi-Mian Li, Han-Shuo Yang, Yu-Quan Wei

  Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition. 09/2011; 42(5):594-8.

  To study molecular mechanisms underlying the extravasation of mice melanoma cells during lung metastasis. B16-RED melanoma cell line was established which stably express the red fluorescent protein.To study molecular mechanisms underlying the extravasation of mice melanoma cells during lung metastasis. B16-RED melanoma cell line was established which stably express the red fluorescent protein. B16-RED cells were compared with B16 cells in ability of proliferation and lung metastasis. A mouse lung metastasis model was established with B16-RED melanoma cells. FITC-dextran was injected i.v. and CD31 indirect immunoflourescence (IIF) staining was made to identify the location of the tumor cells and the time of tumor cell extravasation. Finally, at 48 hours post cell injection, the lung and a normal lung were removed and used for 32K mice microarray analysis. B16-RED was consistent with B16 in cell shape and ability of proliferation and lung metastasis. 52.7% of B16-RED melanoma cells completed the extravasation within 48 hours in mouse lung metastasis model. Many important signal pathways were involved during lung metastasis, including leukocyte transendothelial migration, MAPK signaling pathway, neuroactive ligand-receptor interaction, focal adhesion, cytokine-cytokine receptor interaction, regulation of actin cytoskeleton, axon guidance, calcium signaling pathway, tight junction, etc. The extravasation during metastasis is a complex and multiple-steps process, in which many important signal pathways in host tissues were involved.

• PUMA Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-x(L) and Mcl-1.

  Authors: Zhu Yuan, Kang Cao, Chao Lin, Lei Li, Huan-Yi Liu, Xin-Yu Zhao, Lei Liu, Hong-Xin Deng, Jiong Li, Chun-Lai Nie, Yu-Quan Wei

  Molecular medicine (Cambridge, Mass.). 08/2011;

  Ovarian cancer is the number one cause of death from gynecologic malignancy. Defective p53 pathway is a hallmark of ovarian carcinoma. p53 mutation correlates significantly with resistance toOvarian cancer is the number one cause of death from gynecologic malignancy. Defective p53 pathway is a hallmark of ovarian carcinoma. p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients. PUMA, a BH3-only Bcl-2 family protein, was recently identified as a transcriptional target of p53 and a potent apoptosis inducer in various cancer cells. In this study, we showed that the induction of PUMA by cisplatin was abolished in p53-deficient SKOV3 cells. Elevated expression of PUMA induced apoptosis and sensitized A2780s and SKOV3 ovarian cancer cells to cisplatin, and the combination of PUMA and low-dose cisplatin significantly suppressed xenograft tumor growth in vivo through enhanced induction of apoptosis compared with treatment with PUMA or cisplatin alone. The effects of PUMA were mediated by enhanced caspase activation and release of cytochrome c and Smac into the cytosol. Furthermore, PUMA chemosensitized intrinsically resistant SKOV3 cells to cisplatin through downregulation of Bcl-x(L) and Mcl-1. PUMA-mediated Bcl-x(L) downregulation mainly happened at the transcription level while PUMA-induced Mcl-1 downregulation was associated with caspase-dependent cleavage and proteasome-mediated degradation. To our knowledge, these data suggest a new mechanism by which overexpression of PUMA enhances sensitivity of SKOV3 cells to cisplatin by lowering the threshold set simultaneously by Bcl-x(L) and Mcl-1. Taken together, our findings indicate that PUMA is an important modulator of therapeutic responses of ovarian cancer cells, and is potentially useful as a chemosensitizer in ovarian cancer therapy.

• Efficient inhibition of human colorectal carcinoma growth by RNA interference targeting polo-like kinase 1 in vitro and in vivo.

  Authors: Wen-Jing Xu, Shuang Zhang, Yang Yang, Na Zhang, Wei Wang, Sheng-Yong Liu, Hong-Wei Tian, Lei Dai, Qian Xie, Xia Zhao, Yu-Quan Wei, Hong-Xin Deng

  Cancer biotherapy & radiopharmaceuticals. 08/2011; 26(4):427-36.

  Polo-like kinase 1 (PLK1) showing a high expression in various kinds of tumors is considered a candidate target for cancer therapy. The aim of our study was to explore the effects of silencing PLK1Polo-like kinase 1 (PLK1) showing a high expression in various kinds of tumors is considered a candidate target for cancer therapy. The aim of our study was to explore the effects of silencing PLK1 gene on human colorectal carcinoma cell line HCT-116 in vitro and in vivo. In vitro, the plasmids generating short hairpin RNA (shRNA)-targeting PLK1 were transfected into HCT-116 by using FugeneHD reagent, and the silencing potency was measured by RT-PCR, western blot, flow cytometry, and Caspase-Glo 3/7 assay, respectively. In vivo, the growth inhibition capacity of PLK1-shRNA on HCT-116 xenograft was measured in nude mice. Then, the silencing effect of PLK1 was analyzed by RT-PCR, western blot, and immunohistochemistry, respectively. Apoptosis, angiogenesis, and proliferation in tumor tissues were measured by TUNEL, CD31, and PCNA stain, respectively. The RNA interference targeting PLK1 significantly decreased the expression of PLK1 in vitro. More importantly, anti-PLK1 treatment in HCT-116 xenograft decreased tumor weight by 81.58% compared with the control group (p<0.001), accompanied with decreased PLK1 mRNA and protein expression, increased cell apoptosis, and reduced angiogenesis and proliferation (p<0.001). Our study showed that knockdown of PLK1 by shRNA might be the potential therapeutic approach against human colorectal carcinoma.

• [RNA interference targeting focal adhesion kinase inhibited the growth of human hepatocellular carcinoma sk-hep-1].

  Authors: Wen-Jing Xu, Shuang Zhang, Na Zhang, Yang Yang, Yu-Quan Wei, Hong-Xin Deng

  Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition. 07/2011; 42(4):455-60.

  To test the impact of silencing focal adhesion kinase (FAK) gene on human hepatocellular carcinoma cell line sk-hep-1 using RNA interference (RNAi) in vitro, and its therapeutic effect on humanTo test the impact of silencing focal adhesion kinase (FAK) gene on human hepatocellular carcinoma cell line sk-hep-1 using RNA interference (RNAi) in vitro, and its therapeutic effect on human hepatocellular carcinoma xenograft in vivo. The plasmids generating short hairpin RNA that target FAK gene were transfected into sk-hep-1 cell line through Fugene HD. The impact was analyzed using flow cytometry, RT-PCR and western bolt. Human hepatocellular carcinoma xenograft in nude mice was established and treated with injection of the plasmids that packaged by cationic liposome into the tail veins the mice. The volumes and weights of the tumors were measured. The tumor tissues were analysed with FAK, CD31 and PCNA immunohistochemistry and TUNEL. The RNAi targeting FAK significantly down regulated the expression of FAK in mRNA and the level of protein (P < 0.001), and increased the cell apoptosis in vitro. The mice treated with pshFAK had slower tumor growth, resulting in smaller tumor size and lower tumor weight (P < 0.001) comparing to the controls. Decrease in FAK protein expression, tumor angiogenesis and proliferation, and increase in tumor apoptosis were found in the mice treated with pshFAK compared to the controls (P < 0.001). The shRNA targeting FAK suppresses the FAK expression of human hepatocellular carcinoma cells sk-hep-1, inhibits tumor growth, and promotes cell apoptosis in vitro and in vivo. FAK could become a candidate target for liver cancer treatment.

• Discovery of novel Pim-1 kinase inhibitors by a hierarchical multistage virtual screening approach based on SVM model, pharmacophore, and molecular docking.

  Authors: Ji-Xia Ren, Lin-Li Li, Ren-Lin Zheng, Huan-Zhang Xie, Zhi-Xing Cao, Shan Feng, You-Li Pan, Xin Chen, Yu-Quan Wei, Sheng-Yong Yang

  Journal of chemical information and modeling. 06/2011; 51(6):1364-75.

  In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vectorIn this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors.

• Enhanced antitumor efficacy by blocking activation of the phosphatidylinositol 3-kinase/Akt pathway during anti-angiogenesis therapy.

  Authors: Yu Wei Zhao, Lu Jin, Zhi Mian Li, Cheng Jian Zhao, Yu Quan Wei, Han Shuo Yang

  Cancer science. 05/2011; 102(8):1469-75.

  Anti-angiogenesis has been a promising strategy for cancer therapy. However, many signal pathways are activated during anti-angiogenic treatment to counteract the therapeutic efficacy. Among theseAnti-angiogenesis has been a promising strategy for cancer therapy. However, many signal pathways are activated during anti-angiogenic treatment to counteract the therapeutic efficacy. Among these pathways, evidence has directly pointed to the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway, whose activation resulted in tolerance to the absence of nutrients and oxygen when tumor angiogenesis has been inhibited. In the present study, we investigated the effects of blocking activation of the PI3K/Akt pathway on cell survival in vitro and tumor growth in vivo during anti-angiogenesis therapy. In modeled microenvironments in vitro, we observed that the phosphorylation of Akt in tumor cells was increased gradually in the absence of serum and oxygen in a time-dependent manner. The specific inhibitors of PI3K inhibited the proliferation of tumor cells in a dose-dependent manner in vitro. Moreover, inhibition was enhanced gradually with increased serum deprivation and/or hypoxia. In a mouse tumor model, we found the phosphorylation of Akt obviously increased following anti-angiogenic therapy using plasmids encoding soluble vascular endothelial growth factor receptor-2, but significantly reduced after treatment with LY294002. Consequently, the combinational treatment exhibited better antitumor effects compared with single treatments, presenting larger necrosis-like areas, more apoptotic cells, less microvessel density and less phosphorylated Akt in tumors. These results suggest that blocking activation of the PI3K/Akt pathway during anti-angiogenesis therapy could enhance antitumor efficacy. Thus, targeting the PI3K/Akt pathway might be a promising strategy to reverse tumor resistance to anti-angiogenesis therapy.