74 results on '"Jianting Long"'
Search Results
52. Additional file 6: Figure S2. of miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma
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Chunlin Jiang, Jianting Long, Baoxian Liu, Xu, Ming, Wang, Wei, Xiaoyan Xie, Xiaolin Wang, and Kuang, Ming
- Abstract
(A) Real-time PCR analysis of miR-500a-3p expression in Hep G2 and Huh 7 cells transduced with miR-500a-3p or transfected with anti-miR-500a-3p compared to control. Transcript levels were normalized by U6 expression. Error bars represent the mean ± s.d. of three independent experiments. *P
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- 2017
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53. Liposome-based co-delivery of siRNA and docetaxel for the synergistic treatment of lung cancer
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Shi Fang, Rui-Fang Zeng, Jianting Long, Qiang-Sheng Dai, Mei-Hua Qu, and Heping Li
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Small interfering RNA ,Lung Neoplasms ,Mice, Nude ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Docetaxel ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Cell Proliferation ,A549 cell ,Mice, Inbred BALB C ,Liposome ,Dose-Response Relationship, Drug ,Cell growth ,business.industry ,Drug Synergism ,Neoplasms, Experimental ,Rats ,Liposomes ,Cancer cell ,Taxoids ,Drug Screening Assays, Antitumor ,business ,medicine.drug - Abstract
Combination of more than one therapeutic strategy is the standard treatment in clinics. Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a nanoparticulate system will suppress the tumor growth. In the present study, docetaxel (DTX) and BCL-2 siRNA was incorporated in a PEGylated liposome to systemically deliver in a lung cancer model (A549). The resulting nanoparticle (lipo-DTX/siRNA) was stable and exhibited a sustained release profile. The co-delivery of therapeutic moieties inhibited the cell proliferation (A549 and H226) in a time-dependent manner. Moreover, the co-delivery system of DTX and siRNA exhibited a remarkable apoptosis of cancer cells with elevated levels of caspase 3/7 activity (apoptosis markers). Cell cycle analysis further showed remarkable increase in sub-G0/G1 phase, indicating increasing hypodiploids or apoptotic cells. Pharmacokinetic study showed a long circulating profile for DTX from lipo-DTX/siRNA system facilitating the passive tumor targeting. In vivo antitumor study on A549 cell bearing xenograft tumor model exhibited a remarkable tumor regression profile for lipo-DTX/siRNA with 100% survival rate. The favorable tumor inhibition response was attributed to the synergistic effect of DTX potency and MDR reversing ability of BCL-2 siRNA in the tumor mass. Overall, experimental results suggest that co-delivery of DTX and siRNA could be promising approach in the treatment of lung cancers.
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- 2014
54. XPC gene polymorphisms contribute to bladder cancer susceptibility: a meta-analysis
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Rui-Fang Zeng, Jianting Long, Zhenwei Peng, Rui-Xi Hua, and Qiang-Sheng Dai
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Risk ,Oncology ,medicine.medical_specialty ,Xeroderma pigmentosum ,Genotype ,Biology ,Bioinformatics ,Internal medicine ,Odds Ratio ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Gene ,Alleles ,Polymorphism, Genetic ,Bladder cancer ,General Medicine ,Odds ratio ,medicine.disease ,Confidence interval ,DNA-Binding Proteins ,Increased risk ,Urinary Bladder Neoplasms ,Meta-analysis ,Publication Bias - Abstract
Numerous studies have investigated the association between three polymorphisms (Lys939Gln, Ala499Val and PAT−/+) of Xeroderma pigmentosum group C (XPC) gene and bladder cancer susceptibility; however, the findings are inconclusive. In order to acquire a more precise estimation of the relationship, we performed a meta-analysis based on 10 studies including 3,934 cases and 4,269 controls for Lys939Gln, five studies including 2,113 cases and 2,249 controls for Ala499Val, and seven studies including 2,834 cases and 3,048 controls for PAT−/+ polymorphism. We searched publications from EMBASE, MEDLINE, and Chinese Biomedical. We calculated pooled odds ratio (OR) and 95 % confidence interval (CI) by using either fixed-effects or random-effects model according to the between-study heterogeneity. We found that all studied polymorphisms were individually associated with increased overall cancer risks, as shown by ORs (95 % CIs) below: the Lys939Gln (Gln/Gln vs. Lys/Lys: OR = 1.39, 95 % CI = 1.08–1.79; recessive model: OR = 1.42, 95 % CI = 1.11–1.83; and allele comparing: OR = 1.12, 95 % CI = 1.003–1.24), the Ala499Val (Val/Val vs. Ala/Ala: OR = 1.82, 95 % CI = 1.19–2.79; recessive model: OR = 1.70, 95 % CI = 1.18–2.46; and allele comparing: OR = 1.23, 95 % CI = 1.01–1.50), and the PAT−/+ (+/+ vs. −/−: OR = 1.36, 95 % CI = 1.03–1.79 and recessive model: OR = 1.34, 95 % CI = 1.06–1.70). Furthermore, stratification analyses demonstrated an increased risk for Asian populations as to the Lys939Gln and PAT−/+ whereas for Caucasian populations as to the Ala499Val polymorphism in the homozygous and recessive models. Despite some limitations, this meta-analysis suggests that XPC polymorphisms are associated with bladder cancer risk, but this association warrants further validation in well-designed studies with large sample sizes.
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- 2013
55. miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β
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Bo Zhou, Jianyong Yang, Jianting Long, Wei-Xia Zeng, Xian-Cheng Zeng, Wei Chen, Heping Li, Bing Zhang, and Guosheng Tan
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Cancer Research ,Carcinoma, Hepatocellular ,Blotting, Western ,Fluorescent Antibody Technique ,Mice, Nude ,Apoptosis ,Biology ,Real-Time Polymerase Chain Reaction ,Proto-Oncogene Proteins c-myc ,Mice ,Cyclin D1 ,MICROBIOLOGY PROCEDURES ,Downregulation and upregulation ,Cell Movement ,In vivo ,Cell Adhesion ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,RNA, Messenger ,RNA, Small Interfering ,Cell Proliferation ,Mice, Inbred BALB C ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Cell Cycle ,Liver Neoplasms ,NF-kappa B ,General Medicine ,Flow Cytometry ,medicine.disease ,digestive system diseases ,In vitro ,I-kappa B Kinase ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Direct targeting ,Hepatocellular carcinoma ,Immunology ,Cancer research - Abstract
It has been demonstrated that nuclear factor-kappa B (NF-κB), which is overactivated in hepatocellular carcinoma (HCC), plays important roles in the development of HCC. Recently, a group of dysregulated micro RNAs were reported to be involved in HCC progression. Further understanding of micro RNA-mediated regulation of NF-κB pathway may provide novel therapeutic targets for HCC. In this study, we found that miR-451 expression was markedly downregulated in HCC cells and tissues compared with immortalized normal liver epithelial cells and adjacent non- cancerous tissues, respectively. Upregulation of miR-451 inhibited, while downregulation of miR-451 promoted, the tumorigenicity of HCC cells both in vitro and in vivo. These changes in the properties of HCC cells were associated with deregulation of two well-known cellular G1/S transitional regulators, cyclin D1 and c-Myc, which are downstream targets of NF-κB pathway. Furthermore, we demonstrated that miR-451 upregulation led to downregulation of cyclin D1 and c-Myc through inhibition of NF-κB pathway initiated by direct targeting of the IKBKB 3'-untranslated region. Therefore, these results suggest that miR-451 downregulation plays an important role in promoting proliferation of HCC cells and may provide the basis for the development of novel anti-HCC therapies.
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- 2013
56. MicroRNA-210 interacts with FBXO31 to regulate cancer proliferation cell cycle and migration in human breast cancer
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Fang Wang, Jianting Long, Cui Chen, Dayue Liu, and Haoming Xia
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,OncoTargets and Therapy ,miR-210 ,FBXO31 ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,Internal medicine ,microRNA ,Medicine ,Pharmacology (medical) ,cancer migration ,skin and connective tissue diseases ,Gene ,Original Research ,business.industry ,Functional correlation ,Cancer ,Cell cycle ,medicine.disease ,cancer proliferation ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Human breast - Abstract
Dayue Liu,1,* Haoming Xia,1,* Fang Wang,2 Cui Chen,2 Jianting Long2 1Department of Surgery, Breast Disease Center, 2Department of Medicinal Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China *These authors contributed equally tothis work Background: In this study, we investigated the functional correlation between microRNA-210 (miR-210) and gene of F-box protein 31 (FBXO31) in regulating breast cancer.Methods: Dual-luciferase assay and quantitative real-time polymerase chain reaction were used to investigate the binding of miR-210 with FBXO31 and their expression patterns in breast cancer. miR-210 was inhibited in breast cancer T47D and MCF-7 cells to assess its effect on cancer proliferation, cell cycle progression, and migration. FBXO31 was also downregulated in breast cancer cells to examine its effect on miR-210-mediated breast cancer regulation. The interaction between miR-210 and FBXO31 was further investigated by examining the effect of overexpressing miR-210 on FBXO31-induced suppression of breast cancer proliferation.Results: FBXO31 was the downstream target gene of miR-210 in breast cancer. miR-210 and FBXO31 are inversely expressed in breast cancer cell lines. miR-210 downregulation reduced cancer progression, induced cell cycle arrest, and inhibited cancer migration in T47D andMCF-7 cells. Tumor suppression by miR-210 downregulation was reversed by downregulating FBXO31. In FBXO31-overexpressed breast cancer cells, upregulating miR-210 also reversed the tumor-suppressive effect of FBXO31 on breast cancer proliferation.Conclusion: Our work demonstrated that the expression pattern and tumor regulatory functions of miR-210 and FBXO31 are inversely correlated in breast cancer. Keywords: breast cancer, miR-210, FBXO31, cancer proliferation, cancer migration
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- 2016
57. Nutritional Risk Screening in patients with chronic kidney disease
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Rongshao, Tan, Jianting, Long, Shi, Fang, Haiyan, Mai, Wei, Lu, Yan, Liu, Jianrui, Wei, and Feng, Yan
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Adult ,Male ,Malnutrition ,Nutritional Status ,Comorbidity ,Middle Aged ,Risk Assessment ,Severity of Illness Index ,Nutrition Assessment ,Prevalence ,Humans ,Female ,Prospective Studies ,Renal Insufficiency, Chronic - Abstract
Knowledge concerning nutritional status of patients with chronic kidney disease (CKD) is limited. Nutritional Risk Screening-2002 (NRS-2002) has been used to evaluate the nutritional aspects of patients according to the recommendation of European Society for Clinical Nutrition and Metabolism. Here we aim to assess the prevalence and characteristics of nutritional risk in CKD patients by using NRS-2002. NRS-2002 scores of 292 CDK patients were recorded in first 24 hours subsequent to their admission to hospital. All patients have never been on dialysis. BMI, weight and various biochemical parameters were also characterized for these patients. Possible correlations between these parameters and NRS-2002 score were investigated. The overall prevalence of nutritional risk was 44.9% (53.6% in CKD stage 4-5 patients and 38.3% in stage 1-3 patients). Statistically significant differences were found in serum Albumin, Haemoglobin B, and lymphocyte counts between patients with or without increased nutritional risk. Under the situation that attending physicians were completely unaware of NRS-2002 scores, only 35.1% of the patients at risk received nutritional support. The nutritional risk status was associated with CKD stages but independent from primary diagnosis type. More attention should be paid to the nutritional status in CKD patients (including early stage patients). We recommended using NRS-2002 for nutritional risk assessment among non-dialysis CKD patients in routine clinical practice.目前人们对于慢性肾脏病患者(CKD)的营养状况了解非常有限。根据欧洲 临床营养与代谢协会推荐,营养风险筛查标准NRS-2002 已被广泛应用于评估 其他疾病患者的营养风险。本研究旨在利用NRS-2002 评估CKD 患者的营养 风险。我们针对292 例未经过透析的CDK 患者进行了NRS-2002 评估,记录 了他们的体重指数(BMI)和各种生化指标,并对NRS-2002 评分与各种指标 之间的相关性进行了分析。在所有样本中,处于营养风险状态的患者比例为 44.9%(CKD 4-5 级患者中比例为53.6%,1-3 级为38.3%)。血清白蛋白、血 红蛋白B 和淋巴细胞计数与患者的营养风险状态显著相关。在主治医师未得 知NRS-2002 评分的状况下,仅有35.1%存在营养风险的患者接受了营养支持 治疗。患者的营养风险状况与其初诊类型无关。本研究结果表明,临床实践 中应该重视CKD 患者(包括早期病人)的营养状况,及时给予营养治疗。我 们建议针对非透析的CKD 患者使用NRS-2002 进行营养风险评估。.
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- 2016
58. The Wilms Tumor-1 (WT1) rs16754 polymorphism is a prognostic factor in acute myeloid leukemia (AML): a meta-analysis
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Qiang-Sheng Dai, Shi Fang, Shenming Wang, Jianting Long, Wanshou Zhu, and Xiaolian Liu
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Oncology ,Male ,Pediatrics ,Time Factors ,0302 clinical medicine ,Risk Factors ,Odds Ratio ,Medicine ,Young adult ,Child ,Myeloid leukemia ,Middle Aged ,Leukemia, Myeloid, Acute ,Phenotype ,Treatment Outcome ,030220 oncology & carcinogenesis ,Meta-analysis ,Disease Progression ,Female ,Wilms tumor gene 1 ,Research Paper ,Adult ,medicine.medical_specialty ,Prognostic factor ,Adolescent ,acute myeloid leukemia ,Polymorphism, Single Nucleotide ,Risk Assessment ,Disease-Free Survival ,03 medical and health sciences ,Young Adult ,Internal medicine ,Humans ,Genetic Predisposition to Disease ,WT1 Proteins ,Genetic Association Studies ,Chi-Square Distribution ,business.industry ,Case-control study ,association ,Wilms' tumor ,Odds ratio ,Protective Factors ,medicine.disease ,meta-analysis ,Case-Control Studies ,business ,Chi-squared distribution ,030215 immunology - Abstract
Although a number of studies suggested that WT1 rs16754 polymorphism might be related to decreased relapse free survival (RFS) and overall survival (OS). The results remain controversial. Published reports were searched in PubMed, EMBASE, and Google Scholar. Twelve publications with 3903 patients had met the inclusion criteria and were subjected to further examination. We found WT1 rs16754 polymorphism was significantly associated with OS in AML (OR = 0.62; 95% CI 0.52 - 0.75; p < 0.00001; I2 = 47%). WT1 rs16754 polymorphism was also significantly associated with RFS in AML (OR = 0.69; 95% CI 0.57 - 0.83; p < 0.001; I2 = 46%). In the subgroup analyses of age, race, and subtype of AML, WT1 rs16754 polymorphism was a independent favorable-risk marker. In conclusion, WT1 rs16754 polymorphism is associated with better survival of AML. It could be used as a cost-effective prognostic biomarker for AML.
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- 2015
59. SphK1 promotes tumor cell migration and invasion in colorectal cancer
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Jianting Long, Junmei Yin, Ying Xie, Shi Fang, and Wei Lu
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0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Colorectal cancer ,Cell Survival ,Gene Expression ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,RNA, Messenger ,RNA, Small Interfering ,biology ,Sphingosine ,Oncogene ,business.industry ,Cell growth ,Cell migration ,General Medicine ,medicine.disease ,digestive system diseases ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Sphingosine kinase 1 ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Carcinogenesis ,business ,Colorectal Neoplasms - Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. Sphingosine kinase 1 (SphK1), which phosphorylates sphingosine to sphingosine-1-phosphate (S1P), is overexpressed in various types of cancers and may act as an oncogene in tumorigenesis. However, little is known about the role of SphK1 in CRC patients. We studied the expression of SphK1 in 85 cases of CRC tissues by immunohistochemistry, qRT-PCR, and western blot. We also evaluated the effect of SphK1 on cell proliferation and invasion by MTT and transwell invasion assay. SphK1 is overexpressed in CRC tissues and cell lines, and upregulation of SphK1 correlated significantly with the following parameters: lymph node metastasis, liver metastasis, and advanced TNM stage. SphK1 knockdown results in inhibition of cancer cell proliferation. Inhibition of CRC cell migration and invasion is also evident through reversal of EMT by increases in E-cadherin expression and decreases in vimentin expression. In conclusion, SphK1 is associated with the proliferation and invasiveness of CRC cells and the SphK1 gene may contribute to a novel therapeutic approach against CRC.
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- 2015
60. MiR-32 contributed to cell proliferation of human breast cancer cells by suppressing of PHLPP2 expression
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Zhefu Ma, Jianting Long, Haoming Xia, Ruifen Zhang, and Xiaosong Yang
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Oncology ,Adult ,medicine.medical_specialty ,Time Factors ,Down-Regulation ,Breast Neoplasms ,Transfection ,Retinoblastoma Protein ,Gene Expression Regulation, Enzymologic ,Cyclin D1 ,Breast cancer ,Downregulation and upregulation ,Internal medicine ,microRNA ,medicine ,Phosphoprotein Phosphatases ,Humans ,Phosphorylation ,3' Untranslated Regions ,Cell Proliferation ,Pharmacology ,Binding Sites ,biology ,Retinoblastoma protein ,General Medicine ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Tumor progression ,Case-Control Studies ,Cancer cell ,biology.protein ,Cancer research ,MCF-7 Cells ,Ectopic expression ,Female ,RNA Interference ,Signal Transduction - Abstract
MicroRNAs (miRNAs) have been identified as important regulators that potentially play critical roles in various biological and pathological processes of cancer cells. The aim of the present study was to investigate the expression of miR-32 in breast cancer and its biological role in tumor progression. MiR-32 expression was markedly upregulated in breast cancer tissues and breast cancer cells. Ectopic expression of miR-32 promoted cell proliferation of breast cancer, whereas miR-32-in suppressed this function. Mechanically, data from luciferase reporter assays revealed that miR-32 directly targeted to the 3'-untranslated region (3'-UTR) of PHLPP2. Overexpression of miR-32 led to downregulation of PHLPP2 protein, which resulted in the downregulation of p21 and upregulation of cyclin D1 and p-Rb. In functional assays, PHLPP2-silenced in miR-32-in-transfected ZR-75-30 cells have positive effect to promote cell proliferation, suggesting that direct PHLPP2 downregulation is required for miR-32-induced cell proliferation of breast cancer. Our findings highlighted the importance of miR-32 in promoting tumor progression, and implicate miR-32 as a potential therapeutic target in breast cancer.
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- 2015
61. Mcl-1 Is a Novel Target of miR-26b That Is Associated with the Apoptosis Induced by TRAIL in HCC Cells
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Jianting Long, Ming Kuang, Baoxian Liu, Xiaoyan Xie, and Chunlin Jiang
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Programmed cell death ,Carcinoma, Hepatocellular ,Article Subject ,lcsh:Medicine ,Apoptosis ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,TNF-Related Apoptosis-Inducing Ligand ,hemic and lymphatic diseases ,microRNA ,medicine ,Humans ,Viability assay ,neoplasms ,General Immunology and Microbiology ,medicine.diagnostic_test ,lcsh:R ,Liver Neoplasms ,Hep G2 Cells ,General Medicine ,Transfection ,Molecular biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Drug Resistance, Neoplasm ,Cell culture ,Cancer cell ,Myeloid Cell Leukemia Sequence 1 Protein ,Research Article - Abstract
Aim. To investigate the role of miR-26b and Mcl-1 in TRAIL-inducing cell death in hepatocellular carcinoma.Methods. The expression of miR-26b and Mcl-1 in HCC was detected by RT-qPCR and western blot. The regulation of Mcl-1 by miR-26b was determined by luciferase reporter assay. MTT and flow cytometry were employed to detect the cell viability and apoptosis.Results. miR-26b is commonly downregulated in HCC cell lines compared with the LO2 cell line. In contrast, the Mcl-1 expression is upregulated in HCC cell lines. Bioinformatic analysis identified a putative target site in the Mcl-1 mRNA for miR-26b and luciferase reporter assay showed that miR-26b directly targeted the 3′-UTR (3′-Untranslated Regions) of Mcl-1 mRNA. Transfection of miR-26b mimics suppressed Mcl-1 expression in HCC cells and sensitized the cancer cells to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) cytotoxicity. In addition, transfection of HCC cells with Mcl-1 expression plasmid abolished the sensitization effect of miR-26b to TRAIL-inducing apoptosis.Conclusions. Our study showed that miR-26b was a negative regulator of Mcl-1 gene and sensitized TRAIL-inducing apoptosis in HCC cells, suggesting that the miR-26b-Mcl-1 pathway might be a novel target for the treatment of HCC.
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- 2015
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62. Anticancer drug-loaded multifunctional nanoparticles to enhance the chemotherapeutic efficacy in lung cancer metastasis
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Jianting Long, Shi Fang, Rui-Fang Zeng, Shu-Yu Zhuo, Heping Li, Tuck-Yun Cheang, and Qiang-Sheng Dai
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Lung Neoplasms ,EGFR ,Biomedical Engineering ,Ligand targeting ,Medicine (miscellaneous) ,Pharmaceutical Science ,Mice, Nude ,Bioengineering ,Antineoplastic Agents ,Pharmacology ,Applied Microbiology and Biotechnology ,Metastasis ,Mice ,Immune system ,Epidermal growth factor ,Cell Line, Tumor ,medicine ,Controlled release ,Animals ,Humans ,Doxorubicin ,Neoplasm Metastasis ,Lung cancer ,EGF ,Mice, Inbred BALB C ,Lung ,Inhalation ,Epidermal Growth Factor ,business.industry ,Caspase 3 ,Research ,respiratory system ,medicine.disease ,Xenograft Model Antitumor Assays ,ErbB Receptors ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Molecular Medicine ,Nanoparticles ,Female ,Nanocarriers ,business ,Gelatin nanoparticles ,medicine.drug - Abstract
Background Inhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers. Results The EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group. Conclusions Overall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.
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- 2014
63. Optimization and validation of mitochondria-based functional assay as a useful tool to identify BH3-like molecules selectively targeting anti-apoptotic Bcl-2 proteins
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Jianting Long, Shaomeng Wang, Liu Liu, Sanjeev Shangary, Shenming Wang, Han Yi, and Zaneta Nikolovska-Coleska
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Cytochrome ,Blotting, Western ,Mitochondrial outer membrane permeabilization (MOMP) ,bcl-X Protein ,Apoptosis ,Breast Neoplasms ,Mitochondrion ,Biology ,Mitochondrial Proteins ,Cell Line, Tumor ,Bcl-2 homolog domain 3 (BH3) ,Humans ,Cell-Free System ,Cytochrome c ,Bcl-2 family ,Intracellular Signaling Peptides and Proteins ,Cytochromes c ,Reproducibility of Results ,Surface Plasmon Resonance ,Mitochondria ,Cell biology ,Blot ,B cell lymphoma 2 (Bcl-2) ,Proto-Oncogene Proteins c-bcl-2 ,Cancer cell ,biology.protein ,Myeloid Cell Leukemia Sequence 1 Protein ,Female ,bcl-Associated Death Protein ,biological phenomena, cell phenomena, and immunity ,Apoptosis Regulatory Proteins ,Bacterial outer membrane ,Research Article ,BH3 Interacting Domain Death Agonist Protein ,Biotechnology - Abstract
Background Mitochondrial outer membrane permeabilization (MOMP) is a crucial step leading to apoptotic destruction of cancer cells. Bcl-2 family proteins delicately regulate mitochondrial outer membrane integrity through protein-protein interactions, which makes the mitochondrion an ideal cell-free system for screening molecules targeting the Bcl-2 anti-apoptotic proteins. But assay conditions need to be optimized for more reliable results. In this study, we aimed at establishing a reliable functional assay using mitochondria isolated from breast cancer cells to decipher the mode of action of BH3 peptides derived from BH3-only proteins. In this study, high ionic strength buffer was adopted during the initiation of MOMP. Mitochondria isolated from human breast cancer cell lines with distinct expression patterns of Bcl-2 anti-apoptotic proteins were permeabilized by different BH3 peptides alone or in combination, with or without the presence of recombinant anti-apoptotic Bcl-2 family proteins. Cytochrome C and Smac/Diablo were tested in both supernatants and mitochondrial pellets by Western blotting. Results Sufficient ionic strength was required for optimal release of Cytochrome C. Bad and Noxa BH3 peptides exhibited their bona fide antagonistic effects against Bcl-2/Bcl-xL and Mcl-1 proteins, respectively, whereas Bim BH3 peptide antagonized all three anti-apoptotic Bcl-2 members. Bad and Noxa peptides synergized with each other in the induction of MOMP when mitochondria were dually protected by both Bcl-2/Bcl-xL and Mcl-1. Conclusions This method based on MOMP is a useful screening tool for identifying BH3 mimetics with selective toxicity against breast cancer cell mitochondria protected by the three major Bcl-2 anti-apoptotic proteins.
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- 2013
64. Poly (AT) deletion/insertion polymorphism of the XPC gene contributes to urinary system cancer susceptibility: a meta-analysis
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Zhu-Ming Hua, Rui-Xi Hua, Qiang-Sheng Dai, Cheang Tuck Yun, Jianting Long, Ruoxin Zhang, Rui-Fang Zeng, and Yu-Shan Huang
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medicine.medical_specialty ,Population ,Single-nucleotide polymorphism ,Biology ,Bioinformatics ,Gastroenterology ,Prostate cancer ,INDEL Mutation ,Internal medicine ,Genotype ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Genetic Association Studies ,education.field_of_study ,Bladder cancer ,Polymorphism, Genetic ,General Medicine ,Odds ratio ,medicine.disease ,Hardy–Weinberg principle ,Confidence interval ,DNA-Binding Proteins ,Urinary Bladder Neoplasms ,Case-Control Studies - Abstract
Numerous studies have investigated the association between xeroderma pigmentosum complementation group C (XPC) poly (AT) deletion/insertion (PAT −/+) polymorphism and cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 32 publications including 10,214 cases and 11,302 controls to acquire a more robust estimation of the relationship. We searched publications from MEDLINE, EMBASE and CBM which assessed the associations between XPC PAT −/+ polymorphism and cancer risk. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model. We found that individuals carrying the PAT +/+ genotype have significantly increased cancer risk (PAT +/+ vs. PAT −/−: OR = 1.18, 95% CI = 1.03–1.35 and recessive model: OR = 1.19, 95% CI = 1.06–1.33). Further stratification analysis showed a significantly increased risk for prostate cancer (PAT +/+ vs. PAT −/−: OR = 2.20, 95% CI = 1.39–3.48, recessive model: OR = 2.07, 95% CI = 1.33–3.23 and PAT + vs. PAT −: OR = 1.39, 95% CI = 1.12–1.71), bladder cancer (recessive model: OR = 1.33, 95% CI = 1.03–1.72), Caucasian ethnicity (recessive model: OR = 1.21, 95% CI = 1.02–1.43), population-based studies (recessive model: OR = 1.23, 95% CI = 1.05–1.43) and studies with relatively large sample size (PAT +/+ vs. PAT −/−: OR = 1.18, 95% CI = 1.04–1.35 and recessive model: OR = 1.20, 95% CI = 1.08–1.33). Despite some limitations, this meta-analysis established solid statistical evidence for the association between the XPC PAT +/+ genotype and cancer risk, especially for urinary system cancer, but this association warrants further validation in single large studies.
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- 2013
65. A multicentre assessment of malnutrition, nutritional risk, and application of nutritional support among hospitalized patients in Guangzhou hospitals
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Shi, Fang, Jianting, Long, Rongshao, Tan, Haiyan, Mai, Wei, Lu, Feng, Yan, and Junsheng, Peng
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Adult ,Male ,Quality Control ,China ,Nutritional Support ,Malnutrition ,Nutritional Status ,Middle Aged ,Overweight ,Risk Assessment ,Hospitalization ,Cross-Sectional Studies ,Nutrition Assessment ,Prevalence ,Humans ,Mass Screening ,Female ,Obesity ,Hospitals, Teaching ,Aged - Abstract
To assess nutritional status, the prevalence of nutritional risk, and nutritional support in hospitalized patients in Guangzhou, to determine gender or age associated differences in the prevalence of nutritional risk.A total of 2550 patients admitted during April to December 2008 from six departments (Gastroenterology, Pulmonology, Neurology, Nephrology, General Surgery and Thoracic Surgery) of four teaching hospitals were screened using the Nutritional Risk Screening 2002 tool.Overall prevalence of undernutrition and nutritional risk was 17.8% and 41.5%, respectively. The department of Pulmonology had the highest prevalence of undernutrition (28.2%) and nutritional risk (55.9%). The prevalence of nutritional risk was significantly higher in patients=70 years of age than patients70 years (64.2% vs 32.6%, p0.001). No gender difference in the prevalence of nutritional risk was observed in general. In total, 47.6% of "at risk" and 19.4% of "not at risk" patients received nutritional support. Parenteral nutrition accounted for 88.8% of the nutritional support.The present study documented the prevalence of nutritional risk defined by NRS2002 and inappropriate assignment of nutritional interventions in Guangzhou hospitals.
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- 2013
66. Improvement of HBsAg gene-modified dendritic cell-based vaccine efficacy by optimizing immunization method or the application of β-glucosylceramide
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Bo Zhou, Zhirong Zeng, Bing Zhang, Sizhong Xing, Jianting Long, Heping Li, Wei Chen, Jianyong Yang, and Qiang-Sheng Dai
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HBsAg ,Carcinoma, Hepatocellular ,T cell ,Immunology ,Genetic Vectors ,Glucosylceramides ,Cancer Vaccines ,Viral vector ,Adenoviridae ,Mice ,Immunity ,Medicine ,Animals ,Humans ,Hepatitis B Surface Antigens ,business.industry ,Liver Neoplasms ,Vaccination ,virus diseases ,General Medicine ,Dendritic cell ,Dendritic Cells ,Hep G2 Cells ,Vaccine efficacy ,digestive system diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Treatment Outcome ,Female ,Cancer vaccine ,business - Abstract
Hepatocellular carcinoma (HCC) in China is mostly Hepatitis B virus infection related. The antitumor efficacy of HBsAg gene-modified dendritic cells (DC) has been widely tested both in vitro and in vivo. In this study, we analyzed whether adenoviral vector mediated HBsAg expression would alter cell surface phenotype or autologous T cell stimulating function of mature DCs. Further, the anti-tumor efficacy of pAd-HBsAg-DC-based vaccine was evaluated in mice bearing HBsAg expressing HCC. We also tested whether β-glucosylceramide (β-GC) would enhance the anti-tumor activity of pAd-HBsAg-DC. Results revealed that pAd-HBsAg-DC expressed and secreted HBsAg, while maintaining phenotypic characteristics of mature DCs. Vaccination with pAd-HBsAg-DC conferred specific therapeutic antitumor immunity to animal model bearing HBsAg expressing HCC. The application of β-GC activated mice hepatic NKT cells and enhanced the antitumor activity of pAd-HBsAg-DC. Most importantly, in vivo results showed that the inhibiting effect of pAd-HBsAg-DC vaccination on tumor growth was more significant when applied before tumor inoculation, suggesting that genetically modified DC based therapeutic cancer vaccine may achieve the most optimized antitumor effect when applied before tumor onset, and β-GC may serve as a potent innate immune enhancer for augmenting the antitumor effect of pAd-HBsAg-DC vaccine.
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- 2013
67. Declined Preoperative Aspartate Aminotransferase to Neutrophil Ratio Index Predicts Poor Prognosis in Patients with Intrahepatic Cholangiocarcinoma after Hepatectomy.
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Lingyun Liu, Wei Wang, Yi Zhang, Jianting Long, Zhaohui Zhang, Qiao Li, Bin Chen, Shaoqiang Li, Yunpeng Hua, Shunli Shen, and Baogang Peng
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ASPARTATE aminotransferase ,NEUTROPHILS ,CHOLANGIOCARCINOMA ,HEPATECTOMY ,CARCINOEMBRYONIC antigen - Abstract
Purpose Various inflammation-based prognostic biomarkers such as the platelet to lymphocyte ratio and neutrophil to lymphocyte ratio, are related to poor survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aims to investigate the prognostic value of the aspartate aminotransferase to neutrophil ratio index (ANRI) in ICC after hepatic resection. Materials and Methods Data of 184 patients with ICC after hepatectomy were retrospectively reviewed. The cut-off value of ANRI was determined by a receiver operating characteristic curve. Preoperative ANRI and clinicopathological variables were analyzed. The predictive value of preoperative ANRI for prognosis of ICC was identified by univariate and multivariate analyses. Results The optimal cut-off value of ANRI was 6.7. ANRI was associated with tumor size, tumor recurrence, white blood cell, neutrophil count, aspartate aminotransferase, and alanine transaminase. Univariate analysis showed that ANRI, sex, tumor number, tumor size, tumor differentiation, lymph node metastasis, resection margin, clinical TNM stage, neutrophil count, and carcinoembryonic antigen were markedly correlated with overall survival (OS) and disease-free survival (DFS) in patients with ICC. Multivariable analyses revealed that ANRI, a tumor size > 6 cm, poor tumor differentiation, and an R1 resection margin were independent prognostic factors for both OS and DFS. Additionally, preoperative ANRI also had a significant value to predict prognosis in various subgroups of ICC, including serum hepatitis B surface antigen-negative and preoperative elevated carbohydrate antigen 19-9 patients. Conclusion Preoperative declined ANRI is a noninvasive, simple, and effective predictor of poor prognosis in patients with ICC after hepatectomy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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68. The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization of rat hindlimb ischemia model
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Sanming Wang, Hui Zhang, Yuanqi Zhang, Shenming Wang, Xiang-xia Liu, and Jianting Long
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Male ,Vascular Endothelial Growth Factor A ,endocrine system ,medicine.medical_specialty ,Time Factors ,Angiogenesis ,Neovascularization, Physiologic ,Hindlimb ,Transfection ,Andrology ,Neovascularization ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Ischemia ,Laser-Doppler Flowmetry ,Medicine ,Animals ,RNA, Messenger ,Progenitor cell ,Muscle, Skeletal ,Cells, Cultured ,business.industry ,Endothelial Cells ,Genetic Therapy ,Recovery of Function ,Surgery ,Rats ,Heme oxygenase ,Transplantation ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Disease Models, Animal ,chemistry ,Gene Expression Regulation ,Regional Blood Flow ,embryonic structures ,Heme Oxygenase (Decyclizing) ,cardiovascular system ,medicine.symptom ,business ,Cardiology and Cardiovascular Medicine ,Biomarkers ,Blood Flow Velocity ,circulatory and respiratory physiology ,Stem Cell Transplantation - Abstract
ObjectiveTo explore the therapeutic potential of endothelial progenitor cells (EPCs) transfected with vascular endothelial growth factor A (VEGFA) and heme oxygenase-1 (HO-1) on rat hindlimb ischemia model.MethodsEukaryotic expression vectors encoding VEGFA or HO-1 were constructed and introduced into EPCs isolated from rat bone marrow. In total, 150 Sprague Dawley rat hindlimb ischemia models were established and randomized into five groups which were injected via tail vein with phosphate-buffered saline (PBS), nontransfected EPCs, VEGFA-modified EPCs, HO-1-modified EPCs, and both VEGFA- and HO-1-modified EPCs, respectively. The microvessel density, the expressions of VEGFA and HO-1 in the ischemic limbs, the recovery of blood flow as evaluated by laser-Doppler perfusion imaging, and the rate of limb salvage were compared among different groups.ResultsTransplantation of both VEGFA- and HO-1-modified EPCs in recipient rats significantly increased the microvessel density (expressed as capillaries/m2 at day 21 after operation, group vascular endothelial growth factor (VEGF)+HO-1, 357 ± 14.1; group VEGF, 253.7 ± 9.9; group HO-1, 255.5 ± 12.5; group EPC, 210.7 ± 10.3; group PBS, 144.3 ± 9.3; P either VEGFA- or HO-1-modified EPC alone > nontransfected EPC > PBS.ConclusionsVEGFA-modified EPC and HO-1-modified EPC synergized with each other in promoting angiogenesis in ischemic limbs of rat hindlimb ischemia model. In addition to VEGF, the introduction of HO-1 in EPC-based transplantation may serve as a novel and useful therapeutic strategy for ischemic disease of lower extremity.Clinical RelevanceGenetically modified endothelial progenitor cell (EPC) is useful in designing strategies to achieve dual purposes in treating peripheral arterial disease: targeted delivery of therapeutic genes using EPC as vehicle, and enhancement on the angiogenic properties of EPC by the expression of therapeutic genes. Heme oxygenase-1 (HO-1) has been shown to play an important role in ischemic angiogenesis, aside from its role as an antioxidant protein. We have shown for the first time that vascular endothelial growth factor A-modified EPC and HO-1-modified EPC synergized with each other in promoting angiogenesis in rat hindlimb ischemia model. These findings provide further evidence of the importance of both HO-1 and vascular endothelial growth factor in neovascularization.
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- 2012
69. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia
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Brian Parkin, Peter Ouillette, Sami N. Malek, Harry P. Erba, Jianting Long, Dale L. Bixby, Shaomeng Wang, and Kerby Shedden
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Male ,Indoles ,Apoptosis ,Cell Cycle Proteins ,Biochemistry ,Piperazines ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Nuclear protein ,Cells, Cultured ,Aged, 80 and over ,Hematology ,Myeloid Neoplasia ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Imidazoles ,Nuclear Proteins ,Proto-Oncogene Proteins c-mdm2 ,Middle Aged ,Flow Cytometry ,Leukemia ,Leukemia, Myeloid ,Acute Disease ,Mdm2 ,Female ,Adult ,medicine.medical_specialty ,Immunology ,Immunoblotting ,Myelogenous ,Young Adult ,Internal medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Humans ,Spiro Compounds ,neoplasms ,Aged ,Cancer ,Cell Biology ,medicine.disease ,fms-Like Tyrosine Kinase 3 ,Drug Resistance, Neoplasm ,Fms-Like Tyrosine Kinase 3 ,biology.protein ,Cancer research ,Tumor Suppressor Protein p53 ,Ex vivo - Abstract
The survival of most patients with acute myelogenous leukemia (AML) remains poor, and novel therapeutic approaches are needed to improve outcomes. Given that the fraction of AML with mutated p53 is small (∼ 10%), it appears rational to study MDM2 inhibitors as therapy for AML. Here, we report results of a detailed characterization of sensitivity and resistance to treatment ex vivo with the MDM2 inhibitor MI219 in AML blasts from 109 patients. In line with previous observations, all AML cases with mutated p53 were resistant to MI219. Importantly, approximately 30% of AML cases with unmutated p53 also demonstrated primary resistance to MI219. Analysis of potential mechanisms associated with MI219 resistance in AML blasts with wild-type p53 uncovered distinct molecular defects, including low or absent p53 protein induction after MDM2 inhibitor treatment or external irradiation. Furthermore, a separate subset of resistant blasts displayed robust p53 protein induction after MI219 treatment, indicative of defective p53 protein function or defects in the apoptotic p53 network. Finally, analysis of very sensitive AML cases uncovered a strong and significant association with mutated Flt3 status (Flt3-ITD), which for the first time identified a clinically high-risk group of AML that may particularly benefit from MDM2 inhibitor treatment.
- Published
- 2010
70. Clinicopathological significance of p14ARF expression in lung cancer: a meta-analysis.
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Fang Wang, Heping Li, Jianting Long, and Sheng Ye
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TUMOR suppressor proteins ,CLINICAL pathology ,MEDICAL databases ,META-analysis - Abstract
p14
ARF , a tumor suppressor protein, encoded by the p16 tumor suppressor gene, has been reported to be associated with the clinicopathological features of lung cancer. However, the evaluated outcomes were inconsistent and remained inconclusive. In this study, we conducted a meta-analysis to clarify the significance of p14ARF expression in lung cancer pathogenesis. Materials and methods: Electronic databases, PubMed, Web of Knowledge, Embase, and CNKI, were retrieved to collect relevant articles with inclusion and exclusion criteria. Using Stata 12.0 software, 95% confidence intervals (CIs) and odds ratios (ORs) were calculated. Results: A total of 15 eligible case-control studies that evaluated the relationship between p14ARF expression and lung cancer were included in the meta-analysis. The results demonstrated that there were significant associations between p14ARF expression and the risk of non-smallcell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous carcinoma (for NSCLC, OR =11.02, 95% CI =5.30-22.92; for lung adenocarcinoma, OR =7.28, 95% CI =3.92-13.50; and for lung squamous carcinoma, OR =14.40, 95% CI =2.83-73.24). In the stratified analysis based on race, significant associations between p14ARF expression and lung cancer risk were found in Chinese population and Caucasians (for Chinese population, OR = 7.02, 95% CI =4.48-11.00 and for Caucasians, OR =4.19, 95% CI =1.42-12.38). Furthermore, the expression of p14ARF was significantly associated with the TNM-stage of lung cancer in Chinese population (OR =2.07, 95% CI =1.38-3.10). Conclusion: p14ARF expression was significantly associated with the risk of lung cancer. In addition, the data of the meta-analysis showed that there was a significant correlation between p14ARF expression and the TNM-stage of lung cancer in Chinese population. [ABSTRACT FROM AUTHOR]- Published
- 2017
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71. MicroRNA-210 interacts with FBXO31 to regulate cancer proliferation cell cycle and migration in human breast cancer.
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Dayue Liu, Haoming Xia, Fang Wang, Cui Chen, and Jianting Long
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BREAST cancer research ,MICRORNA ,CANCER cell proliferation ,CANCER cell migration ,HUMAN cell cycle - Abstract
Background: In this study, we investigated the functional correlation between microRNA-210 (miR-210) and gene of F-box protein 31 (FBXO31) in regulating breast cancer. Methods: Dual-luciferase assay and quantitative real-time polymerase chain reaction were used to investigate the binding of miR-210 with FBXO31 and their expression patterns in breast cancer. miR-210 was inhibited in breast cancer T47D and MCF-7 cells to assess its effect on cancer proliferation, cell cycle progression, and migration. FBXO31 was also downregulated in breast cancer cells to examine its effect on miR-210-mediated breast cancer regulation. The interaction between miR-210 and FBXO31 was further investigated by examining the effect of overexpressing miR-210 on FBXO31-induced suppression of breast cancer proliferation. Results: FBXO31 was the downstream target gene of miR-210 in breast cancer. miR-210 and FBXO31 are inversely expressed in breast cancer cell lines. miR-210 downregulation reduced cancer progression, induced cell cycle arrest, and inhibited cancer migration in T47D and MCF-7 cells. Tumor suppression by miR-210 downregulation was reversed by downregulating FBXO31. In FBXO31-overexpressed breast cancer cells, upregulating miR-210 also reversed the tumorsuppressive effect of FBXO31 on breast cancer proliferation. Conclusion: Our work demonstrated that the expression pattern and tumor regulatory functions of miR-210 and FBXO31 are inversely correlated in breast cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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72. Abstract LB-204: Highly potent and optimized small-molecule inhibitors of MDM2 achieve complete tumor regression in animal models of solid tumors and leukemia
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Vincent Ferey, Laurent Debussche, Wei Sun, Xiaqin Li, Peng Zou, Christophe Lengauer, Denzil Bernard, Sanjeev Kumar, Ming Guo, Han Yi, Dajun Yang, Jean-christophe Carry, Shanghai Yu, Liu Liu, Isabelle Meaux, Jianting Long, Brian A. Wood, Odette Dos-Santos, Cedric Barriere, Yujun Zhao, Snmao Kang, Pierre-Yves Abecassis, Jeanne A. Stuckey, Lance Leopold, Carlos Garcia-Echeverria, Duxin Sun, Sami N. Malek, Shaomeng Wang, Mel Sorensen, Donna McEachern, and Anne Charlier
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Cancer Research ,biology ,business.industry ,Cancer ,Pharmacology ,medicine.disease ,Small molecule ,Leukemia ,medicine.anatomical_structure ,Oncology ,Prostate ,Toxicity ,Cancer research ,medicine ,Tumor regression ,biology.protein ,Mdm2 ,Sarcoma ,business - Abstract
Activation of p53 by blocking the interaction of MDM2-p53 using non-peptide small-molecule inhibitors is being pursued as a promising new cancer therapeutic strategy. Although genetic activation of p53 has been shown to achieve complete tumor eradication in mice, the best small-molecule inhibitors of the MDM2-p53 interaction reported to date (Nutlins including RG7112 or first generation spiro-oxindoles such as AT219) can only inhibit tumor growth but fail to achieve significant tumor regression in animal models of human cancer. In the present study, we demonstrate, for the first time, that 2 highly optimized spiro-oxindole compounds, Compound A and Compound B, are capable of achieving complete tumor regression or even permanent cure in multiple xenograft models of human cancer (sarcoma, leukemia, prostate) without causing any significant signs of toxicity to animals. They bind to human MDM2 protein with Ki values of Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-204. doi:10.1158/1538-7445.AM2011-LB-204
- Published
- 2011
73. Effect of (-)-gossypol (AT-101) on transcriptional regulation of Noxa and Puma and on Mcl-1-mediated cancer cell resistance to apoptosis
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Jie Chen, J. Jianting Long, Su Qiu, F. Jiang, L. Bai, Donna McEachern, and Shaomeng Wang
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Cancer Research ,biology ,business.industry ,Phases of clinical research ,biology.organism_classification ,chemistry.chemical_compound ,Oncology ,chemistry ,Docetaxel ,Gossypol ,Apoptosis ,hemic and lymphatic diseases ,Puma ,Cancer cell ,Cancer research ,Transcriptional regulation ,Medicine ,Single agent ,business ,medicine.drug - Abstract
e14611 Background: AT-101 is being evaluated in Phase II clinical trials for the treatment of human cancers and demonstrates anticancer activity as a single agent and in combination with docetaxel. Despite extensive investigations, the mechanism of action for its antitumor activity is not completely understood. In this study, we have performed detailed investigations using a panel of human cancer cell lines on the mechanism of action for AT-101. Methods: A series of human breast and prostate cancer cell lines were utilized to evaluate the antitumor activity of AT-101. Cell growth inhibition, cell viability and apoptosis were determined by WST assay, trypan blue assay and flow cytometry, respectively. Gene specific siRNAs were used to knockdown target gene expression. Quantitative RT- PCR was performed to detect the mRNA levels of Puma and Noxa. Co-immunoprecipitation was carried out to detect the association between Mcl-1 and Noxa or Puma. Results: AT-101 induced apoptosis in both Bax/Bak-dependent and -independent manners in a variety of human cancer cell lines concomitant with increased expression of Noxa and Puma in a p53-independent manner. The up-regulation of Noxa was not observed in normal primary breast epithelial cells or normal-like human breast epithelial MCF-12F cells. Transcription inhibitor actinomycin D blocked AT-101-induced up-regulation of Puma and Noxa. Knockdown of Noxa or Puma attenuated AT-101-induced apoptosis. Furthermore, AT-101 effectively overcame Mcl-1-mediated cancer cell resistance to apoptosis. Co-immunoprecipitation studies demonstrated that Mcl-1 specifically associated with Noxa but not Puma. Conclusions: Our findings suggest that transcriptional up-regulation of pro-apoptotic Noxa and Puma contributes to the antitumor activity of AT-101, which plays a dominant role in antagonizing Mcl-1 and overcoming Mcl-1-mediated resistance to apoptosis of cancer cells. AT-101 functions as an antagonist of Bcl-2, Bcl-xL and Mcl-1 through direct binding to these proteins, as well as through upregulation of Noxa and Puma. [Table: see text]
- Published
- 2009
74. Identification of p53 Aberration-Dependent as Well as Non-p53-Mediated Resistance to MDM2 Inhibitors in Acute Myelogenous Leukemia
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Harry P. Erba, Sami N. Malek, Jianting Long, Shaomeng Wang, Brian Parkin, and Peter Ouillette
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biology ,Immunology ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transcriptome ,Exon ,Leukemia ,Myelogenous ,Apoptosis ,medicine ,biology.protein ,Cancer research ,Mdm2 ,SNP - Abstract
MDM2 inhibitors are under development as novel therapeutic agents in cancers and multiple such compounds have entered early-phase clinical trials. AML is characterized by a relatively low incidence of p53 mutations, thus constituting a tumor type that may have high response rates to MDM2 inhibitors. We have measured apoptosis induction following ex-vivo treatment with the MDM2 inhibitors MI63 and MI-219 in highly purified AML blasts from 80 patients using Annexin-V FACS-based readouts at 40 hours post treatment. IC50 values for apoptosis induction were calculated using dose response curves and the program XLfit. Data were integrated with p53 exons 5–9 sequence data and p53 immunoblotting data before and after MDM2 inhibitor treatment. Results: AML blast sensitivities to treatment with MI219 fell into three classes: sensitive with IC50 values 10μM (26/80=32% of all cases). All eight cases with p53 exons 5–9 sequence mutations were resistant to MI-219. p53 immunoblotting analysis before and after MI219 treatment revealed that the vast majority of resistant cases with wild-type p53 exons 5–9 displayed wild-type p53 induction. Conclusion: AML is characterized by a substantial proportion of cases with partial or complete resistance to MDM2 inhibitor treatment. Further, given that the majority of these cases display wild-type p53 induction after MDM2 inhibitor treatment, it can be concluded that post-p53 network defects confer blocks to apoptosis induction in resistant AML blasts. To identify and catalogue these defects we have begun expression array-based analysis of transcriptome differences in sensitive versus resistant cases, SNP 6.0 array-based analyses of genomic aberrations in sensitive versus resistant cases and targeted molecule interrogations. In summary, our data provide important supportive information regarding the planned initiation of human clinical trials with MDM2 inhibitors in AML. Such trials may benefit from ex-vivo testing of AML blasts for sensitivity to MDM2 inhibitors as part of pre-enrollment patient selection.
- Published
- 2008
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