Liu Liu

Publications (13)57.53 Total impact

• Article: A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor.

  Angelo Aguilar, Haibin Zhou, Jianfang Chen, Liu Liu, Longchuan Bai, Donna McEachern, Chao-Yie Yang, Jennifer L Meagher, Jeanne A Stuckey, Shaomeng Wang
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  ABSTRACT: Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with Ki values of < 1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete and durable tumor regression in vivo at a well-tolerated dose-schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.
  Journal of Medicinal Chemistry 02/2013; · 4.80 Impact Factor
• Article: Structure-Based Discovery of BM-957 as a Potent Small-Molecule Inhibitor of Bcl-2 and Bcl-xL Capable of Achieving Complete Tumor Regression.

  Jianfang Chen, Haibin Zhou, Angelo Aguilar, Liu Liu, Longchuan Bai, Donna McEachern, Chao-Yie Yang, Jennifer L Meagher, Jeanne A Stuckey, Shaomeng Wang
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  ABSTRACT: Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K(i) < 1 nM and has low nanomolar IC(50) values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule.
  Journal of Medicinal Chemistry 10/2012; 55(19):8502-14. · 4.80 Impact Factor
• Article: Polymorphisms of tumor necrosis factor gene in primary myelofibrosis.

  Liu Liu, Xiaofei Ai, Zefeng Xu, Zhijian Xiao
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  ABSTRACT: Primary myelofibrosis(PMF) originated from monoclonal hematopoietic stem cell which underwent acquired mutation(1). Tumor necrosis factor, including tumor necrosis factor alpha (TNF-α) and lymphotoxin alpha (LT-α), are the crucial cytokines participate in the pathogenesis of PMF(2). © 2012 John Wiley & Sons A/S.
  European Journal Of Haematology 07/2012; 89(4):367-8. · 2.61 Impact Factor
• Article: Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity.

  Haibin Zhou, Angelo Aguilar, Jianfang Chen, Longchuan Bai, Liu Liu, Jennifer L Meagher, Chao-Yie Yang, Donna McEachern, Xin Cong, Jeanne A Stuckey, Shaomeng Wang
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  ABSTRACT: Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K(i) values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC(50) values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
  Journal of Medicinal Chemistry 07/2012; 55(13):6149-61. · 4.80 Impact Factor
• Article: Correction to Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold.

  Haibin Zhou, Jianfang Chen, Jennifer L Meagher, Chao-Yie Yang, Angelo Aguilar, Liu Liu, Longchuan Bai, Xin Cong, Qian Cai, Xueliang Fang, Jeanne A Stuckey, Shaomeng Wang
  Journal of Medicinal Chemistry 06/2012; 55(12):5987. · 4.80 Impact Factor
• Article: Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold.

  Haibin Zhou, Jianfang Chen, Jennifer L Meagher, Chao-Yie Yang, Angelo Aguilar, Liu Liu, Longchuan Bai, Xin Cong, Qian Cai, Xueliang Fang, Jeanne A Stuckey, Shaomeng Wang
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  ABSTRACT: Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 μM for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with K(i) < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC(50) values of 60-90 nM, and induces robust cell death in the H146 cancer cell line at 30-100 nM.
  Journal of Medicinal Chemistry 03/2012; 55(10):4664-82. · 4.80 Impact Factor
• Source

  Available from: Jianting Miao

  Article: Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: involvement of oxidative stress and cholinergic dysfunction.

  Wei Zhang, Miao Bai, Ye Xi, Jian Hao, Liu Liu, Ni Mao, Changjun Su, Jianting Miao, Zhuyi Li
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  ABSTRACT: A large body of evidence has shown that cognitive deficits occur early, before amyloid plaque deposition, suggesting that soluble amyloid-β protein (Aβ) contributes to the development of early cognitive dysfunction in Alzheimer disease (AD). However, the underlying mechanism(s) through which soluble Aβ exerts its neurotoxicity responsible for cognitive dysfunction in the early stage of AD remains unclear so far. In this study, we used preplaque APPswe/PS1dE9 mice ages 2.5 and 3.5 months to examine alterations in cognitive function, oxidative stress, and cholinergic function. We found that only soluble Aβ, not insoluble Aβ, was detected in these preplaque APPswe/PS1dE9 mice. APPswe/PS1dE9 mice 2.5 months of age did not show any significant changes in the measures of cognitive function, oxidative stress, and cholinergic function, whereas 3.5-month-old APPswe/PS1dE9 mice exhibited spatial memory impairment in the Morris water maze, accompanied by significantly decreased acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) as well as increased malondialdehyde (MDA) and protein carbonyls. In 3.5-month-old preplaque APPswe/PS1dE9 mice, correlational analyses revealed that the performance of impaired spatial memory was inversely correlated with soluble Aβ, MDA, and protein carbonyls, as well as being positively correlated with ACh, ChAT, SOD, and GSH-px; soluble Aβ level was inversely correlated with ACh, ChAT, SOD, and GSH-px, as well as being positively correlated with MDA and protein carbonyls; ACh level showed a significant positive correlation with ChAT, SOD, and GSH-px, as well as a significant inverse correlation with MDA and protein carbonyls. Collectively, this study provides direct evidence that increased oxidative damage and cholinergic dysfunction may be early pathological responses to soluble Aβ and involved in early memory deficits in the preplaque stage of AD. These findings suggest that early antioxidant therapy and improving cholinergic function may be a promising strategy to prevent or delay the onset and progression of AD.
  Free radical biology & medicine 02/2012; 52(8):1443-52. · 5.42 Impact Factor
• Article: Effects of vertical mixing on phytoplankton blooms in Xiangxi Bay of Three Gorges Reservoir: implications for management.

  Liu Liu, Defu Liu, David M Johnson, Zhongqiang Yi, Yuling Huang
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  ABSTRACT: Since the initial filling of Three Gorges Reservoir (TGR), serious phytoplankton blooms have occurred in its tributary bays. Cyanobacteria blooms have been observed in a number of tributary bays and threaten the drinking water security of residents in the TGR region. To identify the key factors controlling phytoplankton blooms in tributary bays and propose an effective management strategy, a one-year water quality study (November 2009 to October 2010) was conducted in Xiangxi Bay (XXB) of TGR. The results show that a rapid decrease in mixing depth is associated with the spring bloom, fading of the fall bloom occurs with the rapid increase in mixing depth, and an extremely shallow mixing depth is associated with cyanobacteria blooms that predominate during the summer. Development of thermal stratification in XXB is the major cause of seasonal variation in mixing depth and density current intrusion from TGR is the major cause of short-term variation in mixing depth. The seasonal thermal stratification of XXB is disrupted by sufficiently large water level fluctuations in TGR. The density current is lifted from mid-depths to the surface and chlorophyll a concentrations rapidly decrease in response. Based on these findings, a conceptual model is proposed for a management strategy to control phytoplankton blooms in tributary bays via controlled releases from TGR.
  Water Research 01/2012; 46(7):2121-30. · 4.86 Impact Factor
• Article: Probing the interactions between chlorpheniramine and 2:1 phyllosilicates.

  Guocheng Lv, Liu Liu, Zhaohui Li, Libing Liao, Meitang Liu
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  ABSTRACT: Interactions between chlorpheniramine (CP), an antihistamine drug used to treat allergy, and 2:1 phyllosilicates were studied under batch kinetic and different solution conditions to investigate the effect of charge density of the substrates on CP removal from solution. The CP removal by Na-montmorillonite was instantaneous, with a very large rate constant and a fast rate, reaching a capacity of 0.64 mmol/g, compared to its cation exchange capacity of 0.85 mmol(c)/g. In contrast, CP removal by talc was 10 times lower at 0.06 mmol/g. Stoichiometric desorption of exchangeable cations accompanying CP removal by Na-montmorillonite confirmed cation exchange as the dominant interaction mechanism. Solution pH had a minimal effect on CP removal by Na-montmorillonite until pH 11. On the contrary, a slight increase in CP removal by talc was observed as the solution pH increased, due to increased negative charges on the pH-dependent surfaces of talc. Interactions between CP and Na-montmorillonite occurred on both external and interlayer sites, resulting in a d-spacing expansion from 12.5 Å to 15.2 Å. In contrast, interactions between CP and talc were only limited to the external surfaces. It was the charge density that ultimately controlled the amount of CP removal by 2:1 phyllosilicates. Thus, montmorillonite offers a superior option for the removal of cationic drugs from aqueous solution.
  Journal of Colloid and Interface Science 01/2012; 374(1):218-25. · 3.07 Impact Factor
• Article: Unique features of primary myelofibrosis in Chinese.

  Zefeng Xu, Robert Peter Gale, Yue Zhang, Tiejun Qin, Huishu Chen, Peihong Zhang, Tianjiao Zhang, Liu Liu, Shiqiang Qu, Zhijian Xiao
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  ABSTRACT: Clinical and laboratory features of 642 consecutive Chinese subjects with primary myelofibrosis (PMF) were analyzed and compared with those of 1054 predominately white subjects with PMF. Chinese subjects were significantly younger, fewer had constitutional symptoms, and fewer had a palpable spleen or liver. Anemia, in contrast, was significantly more common in Chinese as was an increased white blood cell count and low platelet count. The reason for these differences is unclear, but it does not seem to be correlated with delayed diagnosis. A small but significantly increased proportion of Chinese had the JAK2(V617F) mutation but no difference in the frequency of haplotypes associated with PMF in whites. Survival of Chinese with PMF was also significantly longer than that of whites with PMF. We found commonly used staging systems for PMF such as the International Prognostic Scoring System and the Dynamic International Prognostic Scoring System were suboptimal predictors of survival in Chinese with PMF, and we developed a revised prognostic score that should help in comparison of data between studies of PMF in different populations and planning of clinical trials.
  Blood 01/2012; 119(11):2469-73. · 9.90 Impact Factor
• Article: [The effect of MAB225 on radiosensitivity of salivary gland adenoid cystic carcinoma].

  Liu Liu, Xiu-ming Liu, Yan Lv, Hai-sheng Hu, Yi-li Cai
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  ABSTRACT: To observe the effect of epidermal growth factor receptor's monoclonal antibody(MAB225) on radiosensitivity of salivary gland adenoid cystic carcinoma cell. Bi-fluorescence stain ,MTT test and fluorescence flow cytometry(FCM) were used to observe the apoptosis rate and radiosensitizing effect for MAB225 on ACC-2 cell.SPSS11.0 software package was used for data analysis. Through bi-fluorescence stain, MTT test and fluorescence flow cytometry(FCM),it was found that MAB225 combined with radiation treatment produced a 3-fold induction of apoptosis rate, whereas exposure to radiation alone induced apoptosis only 1 fold, compared to the control group. MAB225 enhanced radiosensitivity and decreased survival rates of ACC-2 cell in vitro after radiation.
  Shanghai kou qiang yi xue = Shanghai journal of stomatology 12/2011; 20(6):603-7.
• Source

  Available from: Chen Chen

  Article: Epoxyeicosatrienoic acids attenuate reactive oxygen species level, mitochondrial dysfunction, caspase activation, and apoptosis in carcinoma cells treated with arsenic trioxide.

  Liu Liu, Chen Chen, Wei Gong, Yuanjin Li, Matthew L Edin, Darryl C Zeldin, Dao Wen Wang
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  ABSTRACT: Epoxyeicosatrienoic acids (EETs) and the cytochrome P450 epoxygenase CYP2J2 promote tumorogenesis in vivo and in vitro via direct stimulation of tumor cell growth and inhibition of tumor cell apoptosis. Herein, we describe a novel mechanism of inhibition of tumor cell apoptosis by EETs. In Tca-8113 cancer cells, the antileukemia drug arsenic trioxide (ATO) led to the generation of reactive oxygen species (ROS), impaired mitochondrial function, and induced apoptosis. 11,12-EET pretreatment increased expression of the antioxidant enzymes superoxide dismutase and catalase and inhibited ATO-induced apoptosis. 11,12-EET also prevented the ATO-induced activation of p38 mitogen-activated protein kinase, c-Jun NH(2)-terminal kinase, caspase-3, and caspase-9. Therefore, 11,12-EET-pretreatment attenuated the ROS generation, loss of mitochondrial function, and caspase activation observed after ATO treatment. Moreover, the CYP2J2-specific inhibitor compound 26 enhanced arsenic cytotoxicity to a clinically relevant concentration of ATO (1-2 μM). Both the thiol-containing antioxidant, N-acetyl-cysteine, and 11,12-EET reversed the synergistic effect of the two agents. Taken together, these data indicate that 11,12-EET inhibits apoptosis induced by ATO through a mechanism that involves induction of antioxidant proteins and attenuation of ROS-mediated mitochondrial dysfunction.
  Journal of Pharmacology and Experimental Therapeutics 08/2011; 339(2):451-63. · 3.83 Impact Factor
• Article: Selective inhibitors of CYP2J2 related to terfenadine exhibit strong activity against human cancers in vitro and in vivo.

  Chen Chen, Guiling Li, Wanmin Liao, Jun Wu, Liu Liu, Ding Ma, Jianfeng Zhou, Reem H Elbekai, Matthew L Edin, Darryl C Zeldin, Dao Wen Wang
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  ABSTRACT: The cytochrome P450 epoxygenase, CYP2J2, converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs). We found recently that this enzyme is dramatically up-regulated in a variety of established human carcinoma cell lines and in human cancerous tissue and promotes the neoplastic phenotype. In the present study, we tested the hypothesis that specific inhibitors of CYP2J2 related to the drug terfenadine are effective antitumor agents. Four of these inhibitors (compounds 4, 5, 11, and 26) were tested for effectiveness in vitro and in vivo. In Tca-8113 cells, the CYP2J2 inhibitors decreased EET production by approximately 60%, whereas they had no effect on CYP2J2 mRNA or protein expression. Compound 26 inhibited the proliferation of human tumor cells, reduced their ability to adhere, invade, and migrate, and attenuated activation of epithelial growth factor receptor signal and kinases and phosphatidylinositol 3 kinase/Akt pathways. Inhibition of CYP2J2 also significantly potentiated human tumor cell apoptosis and caused a corresponding increase in caspase-3 activity and change in expression of apoptosis-related proteins Bax and Bcl-2. In murine xenograft models using MDA-MB-435 cells, treatment with compound 26 significantly repressed tumor growth, decreased lung metastasis, and was associated with increased expression of the anticancer genes CD82 and nm23, without causing toxicity. These data suggest that CYP2J2 inhibitors hold significant promise for use in treatment of neoplastic diseases.
  Journal of Pharmacology and Experimental Therapeutics 04/2009; 329(3):908-18. · 3.83 Impact Factor