Yu-Quan Wei

Publications (231)523.9 Total impact

• Article: Cellular Immunotherapy for Carcinoma Using Genetically Modified EGFR-Specific T Lymphocytes.

  Xikun Zhou, Jing Li, Zhen Wang, Zhongwen Chen, Ji Qiu, Yinbing Zhang, Wei Wang, Yu Ma, Nongyu Huang, Kaijun Cui, Jiong Li, Yu-Quan Wei
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  ABSTRACT: Epidermal growth factor receptor (EGFR) is overexpressed in a variety of human malignancies, including pancreatic cancer, breast cancer, colon cancer, and non-small cell lung cancer. Overexpression of EGFR is a predictive marker of therapeutic response and several lines of evidence suggest that EGFR is an excellent target for tumor therapy. However, the effective antitumor capacity of EGFR-specific T cells against EGFR-overexpressing tumor cells has not been fully elucidated. In our previous study, we identified an anti-EGFR single-chain variable fragment (scFv) with specific and high affinity after screening by ribosome display. In this study, the anticancer potential of anti-EGFR scFv was investigated on the basis of cell-targeted therapy. A chimeric antigen receptor (CAR) targeting EGFR was constructed and expressed on the cell membrane of T lymphocytes. These CAR-modified T cells demonstrated antitumor efficacy both in vitro and in vivo. In addition, the safety evaluation showed that CAR-modified lymphocytes have no or very minimal acute systemic toxicity. Taken together, our study provided the experimental basis for clinical application of genetically engineered lymphocytes; moreover, we also evaluate a new and interesting cell therapy protocol.
  Neoplasia (New York, N.Y.) 05/2013; 15(5):544-53. · 5.48 Impact Factor
• Article: YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models.

  You-Zhi Xu, Hong-Jun Lin, Na-Na Meng, Wen-Jie Lu, Guobo Li, Yuan-Yuan Han, Xiao-Yun Dai, Yong Xia, Xiang-Rong Song, Sheng-Yong Yang, Yu-Quan Wei, Luo-Ting Yu, Ying-Lan Zhao
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  ABSTRACT: BACKGROUND AND PURPOSE: Targeted chemotherapy using small-molecule inhibitors of angiogenesis and proliferation is a promising strategy for cancer therapy. EXPERIMENTAL APPROACH: N-methyl-4-(4-(3-(trifluoromethyl)benzamido)phenoxy)picolinamide4- methylbenzenesulfonate (YL529) was developed via computer-aided drug design, de novo synthesis and high-throughput screening. The biochemical, pharmacodynamical, and toxicological profiles of YL529 were investigated using kinase and cell viability assay, zebrafish and mice tumor xenograft models. KEY RESULTS: In vitro, YL529 selectively inhibited the activities of vascular endothelial growth factor receptors VEGFR2/VEGFR3 and serine/threonine kinase RAF kinase. YL529 inhibited VEGF165 -induced phosphorylation of VEGFR2, as well as proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells (HUVECs). It also significantly blocked vascular formation and angiogenesis in zebrafish model. Moreover, YL529 strongly attenuated the proliferation of A549 cell line through disrupting RAF/MEK/MAPK (mitogen-activated protein kinase) pathway. Oral administration of YL529 (37.5-150 mg(-1) ·kg(-1) ·day(-1) ) to nude mice bearing established tumor xenografts significantly prevented the growth (60-80%) of A549, SPC-A1, A375, OS-RC-2 and HCT116 tumors without detectable toxicity. Tumors from animals inoculated with the lung cancer cell lines SPC-A1 and A549 and the colon carcinoma cell line HCT116 revealed that YL529 treatment markedly reduced microvessel density and increased tumor cell apoptosis. CONCLUSIONS AND IMPLICATIONS: YL529, an orally active multikinase inhibitor, shows the therapeutic potential for solid tumors, and warrants further investigation as a candidate anticancer agent.
  British Journal of Pharmacology 04/2013; · 4.41 Impact Factor
• Article: An integrated proteomics and bioinformatics analyses of Hepatitis B Virus X interacting proteins and identification of a novel interactor apoA-I.

  Tao Zhang, Na Xie, Weifeng He, Rui Liu, Yunlong Lei, Hong Tang, Bo Liu, Canhua Huang, Yu-Quan Wei
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  ABSTRACT: HBx is well-known to be a multifunctional protein encoded by HBV and its biological functions are mainly dependent on pleiotropic protein-protein interactions (PPIs); however, the global mapping of HBx-interactome has not been established so far. Thus, in this study, we have identified 127 HBx-interacting proteins by a profound GST pull-down assay coupled with mass spectrometry, and constructed a HBx-interactome network and core apoA-I pathways with a series of bioinformatics approaches. One of the identified HBx-binding partners is apolipoprotein A-I (apoA-I), which has a specific role in lipid and cholesterol metabolism. The HBx-apoA-I protein interaction was confirmed by both GST pull-down and co-immunoprecipitation. The ectopic overexpression of apoA-I can lead to a significant inhibition on HBV secretion concomitant with the reduction of cellular cholesterol level. In addition, HBV can modulate the function of apoA-I through HBx which might interact with the 44-189 residues of apoA-I and result in dysfunction of apoA-I such as decreased self-association ability, increased carbonyl level and impaired lipid-binding ability. Our results demonstrate an integrated physical association of HBx and host proteins, especially a novel interactor apoA-I that may influence the HBV secretion, which would shed new light on exploring the complicated mechanisms of HBV manipulation on host cellular functions. BIOLOGICAL SIGNIFICANCE: HBx is well-known to be a multifunctional protein encoded by HBV and its biological functions are mainly dependent on pleiotropic protein-protein interactions. Although a series of HBx-interacting proteins have been identified, a global characterization of HBx interactome has not been reported. In this study, we have identified a total of 127 HBx-interacting proteins by a profound GST pull-down assay coupled with mass spectrometry, and constructed a HBx-interactome network with a series of bioinformatics approaches. Our results demonstrate an integrated physical association of HBx and host proteins which may help us explore the complicated mechanisms of HBV manipulation on host cellular functions. In addition, we validated one of the identified HBx-binding partners, apolipoprotein A-I (apoA-I), which played a significant inhibitory effect on HBV secretion, indicating a crucial role of the HBx-apoA-I axis in HBV life cycle.
  Journal of proteomics 04/2013; · 5.07 Impact Factor
• Article: Active immunotherapy for mouse breast cancer with irradiated whole-cell vaccine expressing VEGFR2.

  Heng-Xiu Yan, Ping Cheng, Hai-Yan Wei, Guo-Bo Shen, Li-Xin Fu, Jie Ni, Yang Wu, Yu-Quan Wei
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  ABSTRACT: As tumor-associated antigens are not well characterized for the majority of human tumors, polyvalent vaccines prepared with whole-tumor antigens are an attractive approach for tumor vaccination. Vascular endothelial growth factor receptor-2 (VEGFR2), as a model antigen with which to explore the feasibility of immunotherapy, has shown great promise as a tumor vaccine. However, the efficacy of immunotherapy is often not ideal when used alone. In this study, we explored the therapeutic efficacy of an irradiated AdVEGFR2-infected cell vaccine-based immunotherapy in the weakly immunogenic and highly metastatic 4T1 murine mammary cancer model. An adenovirus encoding the VEGFR2 gene (AdVEGFR2) was constructed. Lethally irradiated, virus-infected 4T1 cells were used as vaccines. Vaccination with lethally irradiated AdVEGFR2-infected 4T1 cells inhibited subsequent tumor growth and pulmonary metastasis compared with challenge inoculations. Angiogenesis was inhibited, and the number of CD8+ T lymphocytes was increased within the tumors. Antitumor activity was also caused by the adoptive transfer of isolated spleen lymphocytes. In vitro, the expression of HMGB1 and HSP70 in the AdVEGFR2‑infected 4T1 cells was increased, and was involved in the activation of tumor antigen-specific T-cell immunity. Our results indicate that the immunotherapy based on irradiated AdVEGFR2-infected whole-cancer cell vaccines may be a potentially effective strategy for 4T1 cancer treatment.
  Oncology Reports 04/2013; 29(4):1510-6. · 1.84 Impact Factor
• Article: hPNAS-4 inhibits proliferation through S phase arrest and apoptosis: underlying action mechanism in ovarian cancer cells.

  Lei Li, Den-Bang Chen, Chao Lin, Kang Cao, Yang Wan, Xin-Yu Zhao, Chun-Lai Nie, Zhu Yuan, Yu-Quan Wei
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  ABSTRACT: PNAS-4, a novel pro-apoptotic gene, was activated during the early response to DNA damage. Previous studies have shown that hPNAS-4 can inhibit tumor growth when over-expressed in ovarian cancer cells. However, the underlying action mechanism remains elusive. In this work, we found that hPNAS-4 expression was significantly increased in SKOV3 cells when exposed to cisplatin, methyl methanesulfonate or mitomycin C, and that its overexpression could induce proliferation inhibition, S phase arrest and apoptosis in A2780s and SKOV3 ovarian cancer cells. The S phase arrest caused by hPNAS-4 was associated with up-regulation of p21. p21 is p53-dispensable and correlates with activation of ERK, and activation of the Cdc25A-Cdk2-Cyclin E/Cyclin A pathway, while the pro-apoptotic effects of hPNAS-4 were mediated by activation of caspase-9 and -3 other than caspase-8, and accompanied by release of AIF, Smac and cytochrome c into the cytosol. Taken together, these data suggest a new mechanism by which hPNAS-4 inhibits proliferation of ovarian cancer cells by inducing S phase arrest and apoptosis via activation of Cdc25A-Cdk2-Cyclin E/Cyclin A axis and mitochondrial dysfunction-mediated caspase-dependent and -independent apoptotic pathways. To our knowledge, we provide the first molecular evidence for the potential application of hPNAS-4 as a novel target in ovarian cancer gene therapy.
  Apoptosis 01/2013; · 4.07 Impact Factor
• Article: Synergic antitumor effect of SKLB1002 and local hyperthermia in 4T1 and CT26.

  Wen Nie, Xue-Lei Ma, Ya-Xiong Sang, Yu-Li Li, Xiang Gao, Guang-Chao Xu, Guo-Bo Shen, Hua-Shan Shi, Xiao-Xiao Liu, Feng-Tian Wang, Yu-Quan Wei
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  ABSTRACT: A de novo VEGFR2-inhibited compound SKLB1002 which is independently developed in our laboratory has been described for antiangiogenesis and displays a potent antitumor activity in vivo and in vitro. In the present investigation, we aim to prove that combination therapy of SKLB1002 with hyperthermia plays a synergy as an antitumor agent in solid tumor. In this study, we analyzed their synergetic inhibitory action on human umbilical vein endothelial cells (HUVEC), murine mammary cancer 4T1, murine colon carcinoma CT26 in vitro. Multiply-table tournament was performed to detect cell proliferation in vitro. 4T1 implantation and CT26 implantation in BALB/c mice were used to examine the activity of combination therapy of SKLB1002 with hyperthermia in vivo. Vascular density was determined by CD31 immunohistochemistry. TUNEL was used to measure apoptosis in tumor tissue. Metastasis assay was investigated via measurement of pulmonary metastasis nodules under the microscope. Potential toxicity of combination therapy was observed by histologic analysis of main organs stained with H&E. In vitro, the combination therapy significantly inhibited cell proliferation of HUVEC, 4T1 and CT26. In vivo, 4T1 and CT26 model experiments showed that combination therapy remarkably inhibited tumor growth and prolonged life span. When compared with controls, combination therapy reached 61 % inhibition index of tumor growth against CT26 and 51 % against 4T1. Moreover, it reduced angiogenesis and increased tumor apoptosis and necrosis. It was further found that combination therapy could efficiently prevent tumor from metastasizing to lung. Importantly, it had no toxicity to main organs including heart, liver, spleen, lung and kidney. Combination treatment has been proved to be a novel and strong strategy in clinical antitumor therapy. Our findings suggest that the combination therapy of SKLB1002 with hyperthermia has a synergistic antiangiogenesis, anticancer and promotion of apoptosis efficacy compared with controls. These findings could pave a new way in clinical tumor therapy.
  Clinical and Experimental Medicine 12/2012; · 1.58 Impact Factor
• Article: Structural Optimization and Structure-Activity Relationships of N2-(4-(4- methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine Derivatives, a New Class of Reversible Kinase Inhibitors Targeting both EGFR-Activating and Resistance Mutations.

  Sheng-Yong Yang, Jiao Yang, Li-Jiao Wang, Jing-Jing Liu, Lei Zhong, Ren-Lin Zheng, Yong Xu, Pan Ji, Chun-Hui Zhang, Wen-Jing Wang, Xing-Dong Lin, Lin-Li Li, Yu-Quan Wei
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  ABSTRACT: We describe the structural optimization of a hit compound, N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations, but has poor binding affinity. Structure-activity relationship studies led to the identification of 9-cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro anti-tumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. Our results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.
  Journal of Medicinal Chemistry 11/2012; · 4.80 Impact Factor
• Article: Gene therapy using the human telomerase catalytic subunit gene promoter enables targeting of the therapeutic effects of vesicular stomatitis virus matrix protein against human lung adenocarcinoma.

  Ping Zhang, Jiao Tan, DA-Bing Yang, Zi-Chao Luo, Shan Luo, Ping Chen, Ping Sun, Yi Zhou, Xian-Cheng Chen, Yu-Quan Wei, Yan-Jun Wen
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  ABSTRACT: The catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), is highly active in immortalized cells and more than 90% of human cancer cells, but is quiescent in the majority of normal somatic cells. Thus, the hTERT promoter has been extensively used in targeted cancer gene therapy. Vesicular stomatitis virus (VSV) matrix protein (MP) induces the apoptosis of tumor cells in the absence of other viral components. In our previous studies, we successfully constructed the pVAX-M plasmid from the pVAX plasmid, which expressed wild-type VSV MP (VSV MP is under the control of the CMV promoter) and demonstrated that pVAX-M efficiently suppresses the growth of malignant tumors via the induction of apoptosis in vitro and in vivo. The present study was designed to construct the plasmid phTERTM (VSV MP is under the control of the hTERT promoter) and investigate whether it had a targeted antitumor effect in nude mice bearing human lung adenocarcinoma. In vitro, A549 human lung adenocarcinoma cells were treated with NS, Lip-null, etoposide, Lip-pVAX-M or Lip-phTERT-M, and examined for cell viability through MTT assays or for apoptosis by flow cytometry and TUNEL assays. In vivo, A549 human lung carcinoma models in nude mice were established. Mice were treated with 10 4-weekly intravenous administrations of NS, Lip-null, etoposide (2 mg/kg), Lip-pVAX-M or Lip-phTERT-M. Subsequently, Lip-phTERT-M was found to be the most efficient inhibitor of tumor growth and inducer of tumor cell apoptosis when compared with the other groups in vivo and in vitro (P<0.05). Notably, immunohistochemical staining showed that Lip-phTERT-M significantly limited the overexpression of VSV MP to the tumor tissues and reduced VSV MP expression in other organs in comparison with Lip-pVAX-M (P<0.05). Therefore, it can be concluded that phTERT-M demonstrates a targeted antitumor effect on A549 human lung adenocarcinoma cells. These observations suggest that phTERT-M gene therapy may be a novel and potent strategy for targeting human lung adenocarcinoma.
  Experimental and therapeutic medicine 11/2012; 4(5):859-864.
• Article: Neighbor communities in drug combination networks characterize synergistic effect.

  Jun Zou, Pan Ji, Ying-Lan Zhao, Lin-Li Li, Yu-Quan Wei, Yu-Zong Chen, Sheng-Yong Yang
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  ABSTRACT: Combination therapies are urgently needed for optimal clinical benefit, but an efficient strategy for rational discovery of drug combinations, especially combinations of experimental drugs, is still lacking. Consequently, we proposed here a network-based computational method to identify novel synergistic drug combinations. A large-scale drug combination network (DCN), which provides an alternative way to study the underlying mechanisms of drug combinations, was constructed by integrating 345 drug combination relationships, 1293 drug-target interactions and 15 134 target-protein interactions. It was illustrated that synergistic drugs seldom have identical or directly connected targets, while most targets in DCN can be reached from every other by 2 to 4 edges (interactions). Accordingly, the concept 'neighbor community' was introduced to characterize the relationships between synergistic drugs by specifying the interactions between drug targets and their neighbor proteins in the context of DCN. A subsequent study revealed that the integrated topological and functional properties of neighbor communities can be employed to successfully predict drug combinations. It was shown that this method can achieve 88% prediction accuracy and 0.95 AUC (Area Under ROC Curve), demonstrating its good performance in specificity and sensitivity. Moreover, ten predicted synergistic drug combinations unknown to the method were confirmed by recent literature, and three predicted new combinations of experimental drug BI-2536 were validated by in vitro assays. The results suggested that this method provides a means to explore promising drug combinations at an earlier stage of the drug development process.
  Molecular BioSystems 09/2012; · 3.53 Impact Factor
• Article: In Silico Prediction of Adverse Drug Reactions and Toxicities Based on Structural, Biological and Clinical Data.

  Xin Liu, Zhe Shi, Ying Xue, Ze Rong Li, Sheng Yong Yang, Yu Quan Wei, Yu Zong Chen
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  ABSTRACT: Drug adverse effects (ADEs) and toxicities have been extensively studied from chemical structure, genetic, biological systems and clinical perspectives. The rapid accumulation of chemical, biological and clinical data are highly useful for characterizing and predicting ADEs, and have enabled increasing exploration of computational methods as low cost tools for predicting various ADEs and toxicities. This article reviews the strategies, current progresses, underlying difficulties and future prospects in using computational methods for predicting ADEs and toxicities.
  Current drug safety. 08/2012;
• Article: Comparative proteomic analysis suggests that mitochondria are involved in autosomal recessive polycystic kidney disease.

  Qing-Wei Li, Xiao-Yan Lu, Yong You, Huan Sun, Xin-Yu Liu, Jian-Zhong Ai, Rui-Zhi Tan, Tie-Lin Chen, Mian-Zhi Chen, Hong-Lian Wang, Yu-Quan Wei, Qin Zhou
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  ABSTRACT: Autosomal recessive polycystic kidney disease (ARPKD), characterized by ectatic collecting duct, is an infantile form of PKD occurring in 1 in 20 000 births. Despite having been studied for many years, little is known about the underlying mechanisms. In the current study, we employed, for the first time, a MS-based comparative proteomics approach to investigate the differently expressed proteins between kidney tissue samples of four ARPKD and five control individuals. Thirty two differently expressed proteins were identified and six of the identified protein encoding genes performed on an independent group (three ARPKD subjects, four control subjects) were verified by semi-quantitative RT-PCR, and part of them were further validated by Western blot and immunohistochemistry. Moreover, similar alteration tendency was detected after downregulation of PKHD1 by small interfering RNA in HEK293T cell. Interestingly, most of the identified proteins are associated with mitochondria. This implies that mitochondria may be implicated in ARPKD. Furthermore, the String software was utilized to investigate the biological association network, which is based on known and predicted protein interactions. In conclusion, our findings depicted a global understanding of ARPKD progression and provided a promising resource of targeting protein, and shed some light further investigation of ARPKD.
  Proteomics 06/2012; 12(15-16):2556-70. · 4.43 Impact Factor
• Article: Vector-based miR-15a/16-1 plasmid inhibits colon cancer growth in vivo.

  Lixia Dai, Wei Wang, Shuang Zhang, Qingyuan Jiang, Ruibo Wang, Lei Dai, Lin Cheng, Yang Yang, Yu-Quan Wei, Hong-Xin Deng
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  ABSTRACT: miR-15 (microRNA 15) and miR-16 are frequently deleted or down-regulated in many cancer cell lines and various tumour tissues, suggesting that miR-15a/16-1 plays important roles in tumour progression and might be a method for cancer treatment. We have developed a vector-based plasmid to explore the anti-tumour efficacy of miR-15a/16-1 in colon cancer in vivo. It is proposed that miR-15a and miR-16-1 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 were inversely correlated with CCNB1 expression, and there was consensus between miR-15a/16-1 and CCNB1 mRNA sequences by analysing homology. Vector-based miR-15a/16-1 expression plasmid was constructed and transfected into HCT 116 and SW620 colon cancer cells in vitro. The effects produced on cell viability and angiogenesis were analysed using flow cytometric analysis, colony formation analysis and tube formation analysis. CCNB1 expression down-regulation was checked by Western blotting. Systemic delivery of miR-15a/16-1 plasmids encapsulated in cationic liposome led to a significant inhibition of subcutaneous tumour growth and angiogenesis in tumour tissues, whereas no effects were observed with liposome carrying the non-specific plasmid. In summary, miR-15a/16-1 has been applied in colon cancer treatment in vivo, and resulted in effective colon tumour xenografts growth arrest and angiogenesis decrease. These findings suggest that systemic delivery of vector-based miR-15a/16-1 expression plasmid can be an approach to colon cancer therapy.
  Cell Biology International 05/2012; 36(8):765-70. · 1.48 Impact Factor
• Article: Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat.

  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
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  ABSTRACT: 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, 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.
  International Journal of Oncology 05/2012; 41(2):523-32. · 2.40 Impact Factor
• Article: Cancer microenvironment and cancer vaccine.

  Zhen-Yu Ding, Xue-Lin Zou, Yu-Quan Wei
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  ABSTRACT: 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 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.
  Cancer Microenvironment 05/2012; 5(3):333-44.
• Article: 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.

  Wei-Wei Li, Xiao-Yan 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
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  ABSTRACT: Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute 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 the 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, whose 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.
  Journal of Medicinal Chemistry 03/2012; 55(8):3852-66. · 4.80 Impact Factor
• Article: In vitro and in vivo anti-tumor activities of anti-EGFR single-chain variable fragment fused with recombinant gelonin toxin.

  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
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  ABSTRACT: 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. 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. 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. These results showed that E/rG might have significant potential as a novel clinical therapeutic agent against human NSCLC.
  Journal of Cancer Research and Clinical Oncology 03/2012; 138(7):1081-90. · 2.56 Impact Factor
• Article: (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione protects rats from carbon tetrachloride-induced liver injury and fibrogenesis.

  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
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  ABSTRACT: 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 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.
  World Journal of Gastroenterology 02/2012; 18(7):654-61. · 2.47 Impact Factor
• Article: Enhanced gemcitabine-mediated cell killing of human lung adenocarcinoma by vector-based RNA interference against PLK1.

  Xin-Yu Zhao, Chun-Lai Nie, Shu-Fang Liang, Zhu Yuan, Hong-Xin Deng, Yu-Quan Wei
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  ABSTRACT: Specific PLK1 silencing may be an effective gene therapy modality of treating PLK1-overexpressed cancers. In this study, we first explored the anticancer efficacy of three different short hairpin-expressing plasmids targeting PLK1 in animal model, and then determined the combination therapy effect of gemcitabine with PLK1-shRNA as an adjuvant. Transfection of the PLK1-shRNAs to A549 lung cancer cells induced significant PLK1 depletion, growth inhibition and apoptosis. In vivo administration of PLK1-shRNA constructs to tumor-bearing mice resulted in xenograft regression. Moreover, the combination of PLK1-shRNA plus low-dose gemcitabine (GEM) produced an additive antitumor activity on the lung tumors owing to an inhibition of cancer cell survival and augmented apoptosis. These results indicated a feasible bio-chemotherapeutic strategy for cancer.
  Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 02/2012; · 2.24 Impact Factor
• Article: SKLB1206, a novel orally available multikinase inhibitor targeting EGFR activating and T790M mutants, ErbB2, ErbB4, and VEGFR2, displays potent antitumor activity both in vitro and in vivo.

  Youli Pan, Yong Xu, Shan Feng, Shidong Luo, Renlin Zheng, Jiao Yang, Lijiao Wang, Lei Zhong, Han-Yu Yang, Bing-Lin Wang, Yang Yu, Jingjing Liu, Zhixing Cao, Xiaoyan Wang, Pan Ji, Zerong Wang, Xin Chen, Shuang Zhang, Yu-Quan Wei, Sheng-Yong Yang
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  ABSTRACT: 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 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 oncokinases, including ErbB2, ErbB4, and VEGF receptor 2 (VEGFR2). SKLB1206 exhibited highly antiproliferative 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 antiangiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 showed 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.
  Molecular Cancer Therapeutics 02/2012; 11(4):952-62. · 5.23 Impact Factor
• Article: Novel gene hBiot2 is an independent prognostic factor in colorectal cancer patients.

  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
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  ABSTRACT: 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 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.
  Oncology Reports 02/2012; 27(2):376-82. · 1.84 Impact Factor