19 results on '"Kangdong Liu"'
Search Results
2. Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo
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Fanxiang Yin, Ran Zhao, Dhilli Rao Gorja, Xiaorong Fu, Ning Lu, Hai Huang, Beibei Xu, Hanyong Chen, Jung-Hyun Shim, Kangdong Liu, Zhi Li, Kyle Vaughn Laster, Zigang Dong, and Mee-Hyun Lee
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General Pharmacology, Toxicology and Pharmaceutics - Published
- 2022
3. Inhibition of FGFR1 Activity and Expression by Treatment of β, β-Dimethylacrylalkannin Suppresses Colorectal Cancer Growth in Cells and Patient-Derived Xenograft Mice
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Ran Zhao, Fanxiang Yin, Mangaladoss Fredimoses, Xiaorong Fu, Beibei Xu, Jianhua Zhao, Hanyong Chen, Kangdong Liu, Zhi Li, Joydeb Kumar Kundu, Kyle Vaughn Laster, Zigang Dong, and Mee-Hyun Lee
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- 2023
4. Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms
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Kangdong Liu, Zigang Dong, Ke Yao, and Yifei Xie
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0301 basic medicine ,Cancer Research ,Cancer chemoprevention ,Protein degradation ,Chemoprevention ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Humans ,Medicine ,United States Food and Drug Administration ,business.industry ,Metabolic disorder ,Cancer ,Nutrients ,Metabolism ,medicine.disease ,United States ,Metabolic pathway ,030104 developmental biology ,Oncology ,Anaerobic glycolysis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,business ,Metabolic Networks and Pathways - Abstract
Proliferating cancer cells exhibit metabolic alterations and specific nutritional needs for adapting to their rapid growth. These changes include using aerobic glycolysis, lipid metabolic disorder, and irregular protein degradation. It may be useful to target metabolic abnormalities for cancer chemoprevention. Epidemiological and mechanism-related studies have indicated that many FDA-approved anti-metabolic drugs decrease tumor risk, inhibit tumor growth, or enhance the effect of chemotherapeutic drugs. Drugs targeting nutrient metabolism have fewer side effects with long-term use compared to chemotherapeutic drugs. The characteristics of these drugs make them promising candidates for cancer chemoprevention. Here, we summarize recent discoveries of the chemo-preventive effects of drugs targeting nutrient metabolic pathways and discuss future applications and challenges. Understanding the effects and mechanisms of anti-metabolic drugs in cancer has important implications for exploring strategies for cancer chemoprevention.
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- 2021
5. DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90β
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Liting Zhou, Ning Yao, Lu Yang, Kangdong Liu, Yan Qiao, Chuntian Huang, Ruijuan Du, Yiu To Yeung, Wenting Liu, Dan Cheng, Zigang Dong, and Xiang Li
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General Biochemistry, Genetics and Molecular Biology - Published
- 2023
6. Integrins in cancer: Emerging mechanisms and therapeutic opportunities
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Fangfang Liu, Qiong Wu, Zigang Dong, and Kangdong Liu
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Pharmacology ,Pharmacology (medical) - Published
- 2023
7. Targeting the STAT5A/IDO1 Axis Overcomes Radiotherapy Resistance and Reverses Immunosuppressive Tumor Microenvironment in Non-Small Cell Lung Cancer
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Yang Yang, Xiaoli Zheng, Peizan Ni, Dingjie Li, Qinfu Dan, Xiaohui Wang, Yunhan Wang, Yanan Sun, Kangdong Liu, Zigang Dong, and Hong Ge
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
8. Inhibition of LTA4H by bestatin in human and mouse colorectal cancer
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Ruihua Bai, Simin Zhao, Ann M. Bode, Qiong Wu, Mingyang Yan, H. S. Chen, Seung-Ho Shin, Kangdong Liu, Ziming Dong, Guoguo Jin, Ke Yao, Gangcheng Wang, Dan Li, Zigang Dong, and Zhiping Guo
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Male ,0301 basic medicine ,Research paper ,Colorectal cancer ,Leukotriene B4 ,Receptors, Leukotriene B4 ,Gene Expression ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Epoxide Hydrolases ,Mice, Knockout ,Antibiotics, Antineoplastic ,General Medicine ,Middle Aged ,Prognosis ,Immunohistochemistry ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,Signal transduction ,Colorectal Neoplasms ,Signal Transduction ,Adult ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Leukotriene-A4 hydrolase ,03 medical and health sciences ,Leucine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,neoplasms ,Aged ,Neoplasm Staging ,business.industry ,Leukotriene B4 receptor ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Cancer research ,business ,Carcinogenesis ,Biomarkers - Abstract
Background Our preclinical data showed that the leukotriene A4 hydrolase (LTA4H) pathway plays a role in colorectal cancer (CRC). High expression of LTA4H and leukotriene B4 receptor type 1 (BLT1) were also associated with CRC survival probability. Clinical samples were evaluated to determine whether LTA4H could serve as a therapeutic target and whether leukotriene B4 (LTB4) could be used as a biomarker for evaluating the efficacy of bestatin in CRC. Methods Patients with Stage I-III CRC did or did not receive bestatin prior to surgery. Evaluable pairwise CRC patient blood samples were collected to evaluate LTB4 concentration. Tissues were processed by immunohistochemistry to detect the LTA4H pathway and Ki-67 expression. We also determined whether LTA4H or BLT1 was associated with CRC survival probability and explored the mechanism of bestatin action in CRC. Findings Samples from 13 CRC patients showed a significant decrease in LTB4, the LTA4H signaling pathway, and Ki-67 in the bestatin-treated group compared with the untreated group. LTA4H and BLT1 are overexpressed in CRC and associated with CRC survival probability. Bestatin effectively inhibited LTB4 and tumorigenesis in the ApcMin/+ and CRC patient-derived xenograft mouse model. Interpretation These results demonstrate that LTB4 could serve as a biomarker for evaluating bestatin efficacy in CRC and the antitumor effects of bestatin through its targeting of LTA4H and support further studies focusing on LTA4H inhibition in CRC.
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- 2019
9. 3,3'-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2
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Yuzhou Zhao, Mee-Hyun Lee, Yan Li, Zigang Dong, H. S. Chen, Fayang Ma, Xueyin Zu, Xueli Tian, Naomi Oi, Fangfang Liu, Dong Joon Kim, Kangdong Liu, Ann M. Bode, and Zhi Li
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0301 basic medicine ,Cancer Research ,3,3'-Diindolylmethane ,Indoles ,genetic structures ,MAP Kinase Signaling System ,Colorectal cancer ,Metabolite ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Tumor Cells, Cultured ,medicine ,Animals ,Anticarcinogenic Agents ,Humans ,Cyclooxygenase Inhibitors ,Extracellular Signal-Regulated MAP Kinases ,Cell Proliferation ,Cell growth ,Kinase ,Cell Cycle ,medicine.disease ,In vitro ,030104 developmental biology ,Oncology ,chemistry ,Cyclooxygenase 2 ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Cancer research ,Phosphorylation ,sense organs ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
3,3'-Diindolymethane (DIM) is a dimeric condensation product of indole-3-carbinol (I3C) that is found in broccoli and cabbage. Although DIM has been reported to exhibit anticancer properties against multiple tumor types, the direct target proteins of DIM have not been fully investigated. In the present study, we report that DIM is a novel COX1/2 and ERK1/2 inhibitor that suppresses growth of colon cancer in vitro and in vivo. To identify possible molecular targets of DIM, 11 potential candidate proteins were validated by an in vitro kinase or enzyme assay. We found that DIM directly inhibits COX1/2 and ERK1/2 protein activities in vitro. Additionally, the PGE2 production (COX-mediated metabolite) and phosphorylated RSK expression (ERK1/2 direct downstream kinase) were strongly suppressed by DIM in colon cancer cells. The inhibition of cell growth by DIM is dependent on the expression of COX1/2 or ERK1/2 proteins. Notably, oral administration of DIM suppressed patient-derived xenograft colon tumor growth in an in vivo mouse model. Overall these results suggest that DIM is a potent and dual COX1/2 and ERK1/2 inhibitor that might be used for chemotherapy against colon cancer.
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- 2019
10. Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo
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Xiaoli Ma, H. S. Chen, Dong Joon Kim, Xiaomeng Xie, Kangdong Liu, Feifei Liu, Ann M. Bode, Zigang Dong, Qiong Wu, Ting Wang, Xueyin Zu, Xiangyu Wang, and Yan Zheng
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0301 basic medicine ,Cancer Research ,Esophageal Neoplasms ,Protein Conformation ,MAP Kinase Kinase 3 ,p38 mitogen-activated protein kinases ,Antineoplastic Agents ,Apoptosis ,MAP Kinase Kinase 6 ,Mice, SCID ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Animals ,Humans ,Kinase activity ,Protein Kinase Inhibitors ,Caspase ,Cell Proliferation ,Flavonoids ,Binding Sites ,Gossypetin ,biology ,Cell growth ,Kinase ,Intrinsic apoptosis ,Xenograft Model Antitumor Assays ,Tumor Burden ,G2 Phase Cell Cycle Checkpoints ,Molecular Docking Simulation ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Esophageal Squamous Cell Carcinoma ,Signal transduction ,Apoptosis Regulatory Proteins ,Signal Transduction - Abstract
Gossypetin as a hexahydroxylated flavonoid found in many flowers and Hibiscus. It exerts various pharmacological activities, including antioxidant, antibacterial and anticancer activities. However, the anticancer capacity of gossypetin has not been fully elucidated. In this study, gossypetin was found to inhibit anchorage-dependent and -independent growth of esophageal cancer cells. To identify the molecular target(s) of gossypetin, various signaling protein kinases were screened and results indicate that gossypetin strongly attenuates the MKK3/6-p38 signaling pathway by directly inhibiting MKK3 and MKK6 protein kinase activity in vitro. Mechanistic investigations showed that arginine-61 in MKK6 is critical for binding with gossypetin. Additionally, the inhibition of cell growth by gossypetin is dependent on the expression of MKK3 and MKK6. Gossypetin caused G2 phase cell cycle arrest and induced intrinsic apoptosis by activating caspases 3 and 7 and increasing the expression of BAX and cytochrome c. Notably, gossypetin suppressed patient-derived esophageal xenograft tumor growth in an in vivo mouse model. Our findings suggest that gossypetin is an MKK3 and MKK6 inhibitor that could be useful for preventing or treating esophageal cancer.
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- 2019
11. PHLDA1 Promotes Glioblastoma Oncogenesis via Ras/Mek/Erk Signaling Pathway
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Jiutao Wang, Ning Yao, Yamei Hu, Meixian Wang, Lu Yang, Mingjuan Lei, Satyananda Patel, Xiang Li, Kangdong Liu, and Zigang Dong
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- 2021
12. Targeting EPRS is an Effective Therapeutic Strategy for Gastric Cancer
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Hui Liu, Kangdong Liu, Zigang Dong, Mangaladoss Fredimoses, Dong Joon Kim, Yan Qiao, Peijia Niu, Xueli Tian, and Xiaobing Chen
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Oncogene ,biology ,business.industry ,Wnt signaling pathway ,Cancer ,Helicobacter pylori ,medicine.disease ,biology.organism_classification ,EPRS ,medicine.disease_cause ,medicine ,Cancer research ,Kinase activity ,Signal transduction ,business ,Carcinogenesis - Abstract
Glutamyl-prolyl-tRNA synthetase (EPRS) is part of a multi-synthetase complex that catalyzes the attachment of the cognate amino acid to the corresponding tRNA; however, its role in cancer remains largely unknown. This study was conducted to identify the function, molecular mechanism and potential inhibitors of EPRS in gastric cancer. We believe that our study makes a significant contribution to the literature because we found that EPRS plays a functional role as an oncogene in gastric cancer. We also showed that EPRS accelerates tumor growth by interacting with SCYL2 to enhance kinase activity of GSK-3β and activate the WNT/GSK-3β/β-catenin signaling pathway. Xanthoangelol and 4-hydroxyderricin were identified as effective EPRS inhibitors that restrain gastric cancer patient-derived xenograft tumor growth and Helicobacter pylori combined with alcohol-induced gastric tumorigenesis. Our findings indicate that targeting the EPRS-mediated WNT/GSK-3β/β-catenin signaling pathway is a promising strategy for gastric cancer prevention and therapy. Additionally, xanthoangelol and 4-hydroxyderricin act as effective EPRS inhibitors and chemoprevention reagents, which may be clinically useful for gastric cancer prevention and therapy.
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- 2020
13. Heterogeneity Analysis of Esophageal Squamous Cell Carcinoma for Precision Oncology Research
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Zigang Dong, Huifang Wei, Dong Joon Kim, Qiong Wu, Rendong Yang, Mee-Hyun Lee, Fayang Ma, Fangfang Liu, Kyle Laster, and Kangdong Liu
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Mutation ,Human Protein Atlas ,Cancer ,Computational biology ,Biology ,Esophageal cancer ,medicine.disease_cause ,medicine.disease ,digestive system diseases ,Genotype-phenotype distinction ,medicine ,KEGG ,Carcinogenesis ,neoplasms ,Survival rate - Abstract
Background: Esophageal Squamous Cell Carcinoma (ESCC), which is the most common pathohistological type of esophageal cancer that accounts for roughly 90% of the 456,000 incidents of esophageal cancer cases each year, is a serious malignant disease, with a 15-20% 5-year survival rate worldwide. The outcome of the current established therapeutics for ESCC are not satisfactory. Heterogeneity, including not only the intratumor heterogeneity and complex micro-environment, but also the diversity of heterogeneity across different ESCC samples, is a major biological feature of cancer that is responsible for the establishment of drug resistance and morbidity. Therefore, the diversity of distinct genotypes and phenotypes contributing to this phenomenon should be analyzed for the purpose of precision research and better understanding of ESCC. Methods: Bioinformatic analysis of multi-omics data from The Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA), and Protein Atlas were conducted to investigate heterogeneity across different ESCC samples. Venn Diagrams were utilized to overlap shared and disparate regions of interest between data platforms. DAVID was used for joint functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathways enrichment. The Cytoscape open source software platform and the STRING database were used for integrating and visualizing complex networks with attribute data. Mutation and expression heterogeneity profiles of CCLE-ESCC and TCGA-ESCC samples were analyzed according to matching dissimilarity and correlation distance, respectively. Findings: Heterogeneity at the level of both gene expression and genomic mutations are widespread in the ESCC tumor tissues and established cell lines. In the analysis of animal model data, we observed that there is ambiguity with regards to the source of nearly 50% of identified proteins, which may indicate the existence of trans-species heterogeneity. Our research also indicate that substantial variability exists between different platforms after overlapping sequencing data from cell lines, tumor tissues, normal tissues and PDX tissues of ESCC . Furthermore, Olfactory transduction and Neuroactive ligand-receptor interaction signaling pathways, enriched from the TCGA-ESCC unique proteins, are originally reported in ESCC. Interpretation: Our research found that extensive mutation heterogeneity exists across the samples of ESCC patients and cell lines. The uniquely expressed proteins and relevant signaling pathways provide potential targets for the investigation of carcinogenesis and progression of ESCC. The identification and characterization of genotype and phenotype heterogeneity across different ESCC samples and platforms is essential for developing precise therapeutics for ESCC patients. Funding Statement: This work was supported by National Natural Science Foundation China (NSFC) [No.81872335], Henan Joint Fund [No.U1804196] and Henan Key Science and Technology Program [161100510300]. Declaration of Interests: The authors have no conflict of interest to declare.
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- 2020
14. Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization
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Kangdong Liu, Yiu To Yeung, Bingbing Lu, Chengjuan Zhang, Ruihua Bai, Shuying Yin, Ran Yang, Suyu Fan, Zigang Dong, and Ann M. Bode
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Cyclopropanes ,0301 basic medicine ,Genome instability ,Lung Neoplasms ,p38 mitogen activating protein kinase (MAPK) ,Pyridines ,lcsh:Medicine ,non-small cell lung cancer (NSCLC) ,Non-small cell lung cancer (NSCLC) ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Gefitinib ,Tetraploidization ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Epidermal growth factor receptor ,Lung cancer ,neoplasms ,lcsh:R5-920 ,Gefitinib resistance ,Losmapimod ,biology ,lcsh:R ,General Medicine ,medicine.disease ,respiratory tract diseases ,3. Good health ,030104 developmental biology ,Cancer cell ,Cancer research ,biology.protein ,Erlotinib ,lcsh:Medicine (General) ,Research Paper ,medicine.drug - Abstract
The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38α MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC., Highlights • Gefitinib induces tetraploidy formation in gefitinib-resistant NSCLC cells • YAP-MKK3/6-p38 MAPK signaling is essential for tetraploidization • Losmapimod, a p38 MAPK inhibitor, overcomes gefitinib-resistance both in vitro and PDX xenograft mode Gefitinib is a targeted drug therapy in non-small cell lung cancer (NSCLC) which shows dramatic clinical efficacy. However, most of these patients eventually develop drug resistance. Although researchers have identified different mechanisms contributing to the drug resistance, developing a single therapy to overcome the drug resistance remains difficult. In this study, we find that tetraploidization of cancer cells through YAP-MKK3/6-p38 MAPK signaling could be one of the common mechanisms in developing the drug resistance. By using losmapimod, we could eliminate tetraploidization and overcome gefitinib resistance in an animal model suggesting that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC.
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- 2018
15. A Small Molecule Inhibitor of the β-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo
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Mee-Hyun Lee, Kangdong Liu, Margarita Malakhova, Seung-Ho Shin, H. S. Chen, Ann M. Bode, Ting Wang, Joohyun Ryu, Zigang Dong, Fangfang Liu, Do Young Lim, Mengqiu Song, Kanamata Reddy, and Ki Beom Bae
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0301 basic medicine ,Beta-catenin ,Colorectal cancer ,lcsh:Medicine ,Apoptosis ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Small Molecule Libraries ,Mice ,03 medical and health sciences ,Transcription Factor 4 ,HI-B1 ,Patient-derived xenograft ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Luciferase ,Wnt Signaling Pathway ,beta Catenin ,Cell Proliferation ,lcsh:R5-920 ,Cell growth ,lcsh:R ,Precision medicine ,Wnt signaling pathway ,General Medicine ,β-catenin ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Multiprotein Complexes ,Catenin ,Cancer cell ,Immunology ,Cancer research ,biology.protein ,Small molecule inhibitor ,lcsh:Medicine (General) ,Colorectal Neoplasms ,Research Paper - Abstract
Colorectal cancer is associated with aberrant activation of the Wnt pathway. β-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biological consequences induced by the compound. HI-B1 inhibited β-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. The formation of the β-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with β-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of β-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of β-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the β-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer., Graphical Abstract Image 1, Highlights • HI-B1 is a synthesized compound identified as a β-catenin inhibitor suppressing the β-catenin-TCF4 protein interaction. • HI-B1 preferentially causes apoptosis in β-catenin-dependent cancer cells. • A colon cancer PDX mouse model with a high level of β-catenin is sensitive to HI-B1. β-catenin is an important protein that facilitates colon cancer. Shin et al. synthesized and identified HI-B1 as a direct β-catenin inhibitor. HI-B1 disrupted formation of the β-catenin-TCF4 protein complex. HI-B1 preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. In a comparison of two colon cancer PDX models with different β-catenin levels, they showed that β-catenin-high PDX is more sensitive to HI-B1 treatment than β-catenin-low PDX. HI-B1 could thus be further developed as a colon cancer drug, and β-catenin expression levels might be a predictive biomarker for colon cancer therapy using β-catenin inhibitors.
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- 2017
16. Mefloquine Inhibited Esophageal Squamous Cells Carcinoma Proliferation by Induction of Mitochondrial Autophagy
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Jimin Zhao, Kangdong Liu, Bo Li, Zigang Dong, Zhuo Bao, Xianyu Lu, Zhang Jing, Xinhuan Chen, Yaxing Wei, Yifei Xie, and Qiang Yuan
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In vivo ,Cell growth ,Proteome ,Carcinoma ,medicine ,Clone (cell biology) ,Cancer research ,SDHD ,KEGG ,Biology ,medicine.disease ,Proteomics - Abstract
Background: Esophageal squamous cell carcinoma (ESCC) still has high rates of incidence and mortality, despite developments in medical technology. Therefore, looking for cancer treatment drugs with high efficiency and low toxicity remains very important. In the previous study, we screened FDA-approved drugs, approved for uses other than tumor treatment, and found that mefloquine (MQ), which is used for prevention and treatment of malaria, inhibited clone formation of ESCC cells. Methods: Proteomics and mass spectrometry (MS) were applied to profile proteome changes in ESCC cells after MQ treatment. KEGG was performed to analyse the significantly down-regulated pathways and proteins. Electron microscopy was used to observe mitochondrial changes in MQ-treated KYSE150 cells. And patient derived xenograft (PDX) mouse model was used to observe the anti-tumor effect of MQ in vivo. Findings: MS analyse showed that various proteins changed in MQ-treated KYSE150 cells. KEGG analyse identified dysregulated pathways and proteins. Among these proteins, SDHC, SDHD, MTCO3 and NDUFV3, all known to be essential enzymes in the mitochondrial respiration chain, were involved in these pathways and were notably down-regulated in MQ-treated cells. Meanwhile, mitochondrial autophagy was verified in MQ-treated cells by electron microscopy. Furthermore, MQ significantly inhibited tumor growth in a patient-derived xenograft mouse model of ESCC. All considered, MQ suppressed ESCC cell proliferation by induction of mitochondrial autophagy. Interpretation: Our data suggested that MQ may be a promising drug for ESCC treatment and chemoprevention. Funding Statement: This work was supported by grants from the National Natural Science Foundations of China (No. 81872335, 81572812, and 81472324) and the Natural Science Foundations of Henan (No. 161100510300). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All procedures involving animals in this study were approved by the Animal Ethics Committee.
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- 2019
17. Aurora B Kinase as a Novel Molecular Approach for Osteosarcoma Therapy
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Zigang Dong, Dhilli Rao Gorja, H. S. Chen, Ann M. Bode, Guoguo Jin, Ke Yao, Zhenjiang Zhao, Fangfang Liu, Kanamata Reddy, Zhiping Guo, Keke Wang, and Kangdong Liu
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business.industry ,Cell growth ,Kinase ,medicine.medical_treatment ,Aurora B kinase ,Institutional Animal Care and Use Committee ,Cancer ,Cell cycle ,medicine.disease ,Targeted therapy ,Cancer research ,Medicine ,Osteosarcoma ,business - Abstract
Osteosarcoma is the primary human malignant tumor affecting bone. This cancer most frequently arises in children and adolescents, with a second peak in those over the age of 50. Currently, surgery followed by radiotherapy and chemotherapy are the main treatments, but long-term positive effects are very poor. Aurora B kinase is a serine/threonine kinase that is a key regulator of cell cycle and mitosis. Tissue array analysis revealed that Aurora B kinase is overexpressed in osteosarcoma compared with normal bone tissue. We developed a compound, HOI-07 [i.e., (E)-3-((E)-4-(benzo[d] [1,3]dioxol-5-yl)-2-oxobut-3- en-1-ylidene)indolin-2-one], as a specific Aurora B kinase inhibitor and examined its effectiveness against osteosarcoma cell growth in this study. This compound inhibited Aurora B kinase activity in osteosarcoma and induced apoptosis, caused G2-M phase arrest, and attenuated osteosarcoma anchorage-independent cell growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of osteosarcoma to HOI-07. Results of a xenograft mouse study indicated that HOI-07 treatment effectively suppressed the growth of 143B and KHOS xenografts, without affecting the body weight of mice. The expression of phosphorylated histone H3 (Ser10) was reduced in mice treated with HOI-07. Overall, we identified HOI-07 as a specific Aurora B kinase inhibitor for osteosarcoma treatment and this compound warrants further investigation. Funding Statement: This work was funded by The Hormel Foundation and National Institutes of Health grants CA166011, CA187027, and CA196639 and a Joint Funds of the National Natural Science Foundation of China (Grant No. 162300410337) Declaration of Interests: The authors declare "none." Ethics Approval Statement: Mice were maintained under “specific pathogen-free” conditions based on the guidelines approved by the University of Minnesota Institutional Animal Care and Use Committee. PDX animal studies were preformed following guidelines approved by the Zhengzhou University Institutional Animal Care and Use Committee (Zhengzhou, Henan, China).
- Published
- 2018
18. Circulating Prostaglandin Biosynthesis in Colorectal Cancer and Potential Clinical Significance
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Lei Wang, Haitao Li, Yuqiao Sheng, Paul J. Limburg, Zigang Dong, Naomi Oi, Lisa A. Boardman, Ann M. Bode, Yuzhou Zhao, and Kangdong Liu
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Colorectal cancer ,lcsh:Medicine ,Early detection ,Prostaglandin ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Familial adenomatous polyposis ,Thromboxane A2 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Clinical significance ,neoplasms ,030304 developmental biology ,lcsh:R5-920 ,0303 health sciences ,biology ,business.industry ,lcsh:R ,General Medicine ,medicine.disease ,Predictive value ,digestive system diseases ,3. Good health ,Prostaglandin biosynthesis ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Thromboxane-A synthase ,lcsh:Medicine (General) ,business - Abstract
Background: Colorectal cancer (CRC) represents the third leading cause of cancer-related death in the United States. Lack of reliable biomarkers remains a critical issue for early detection of CRC. In this study, we investigated the potential predictive values of circulating prostaglandin (PG) biosynthesis in CRC risk. Methods: Profiles of circulating PG biosynthesis and platelet counts were determined in healthy subjects (n = 16), familial adenomatous polyposis (FAP) patients who were classified as regular aspirin users (n = 14) or nonusers (n = 24), and CRC patients with (n = 18) or without FAP history (n = 20). Immunohistochemistry staining was performed on biopsy samples. Results: Analysis of circulating PG biosynthesis unexpectedly revealed that CRC progression is accompanied by a pronounced elevation of circulating thromboxane A2 (TXA2) levels. When a circulating TXA2 level of 1000 pg/mL was selected as a practical cutoff point, 95% of CRC patients were successfully identified. Further study suggested that the TXA2 pathway is constitutively activated during colorectal tumorigenesis and required for anchorage-independent growth of colon cancer cells. Conclusions: This study established the importance of the TXA2 pathway in CRC pathophysiology, and laid the groundwork for introducing a TXA2-targeting strategy to CRC prevention, early detection and management.
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- 2015
19. A Chrysin Derivative Suppresses Skin Cancer Growth by Inhibiting Cyclin-dependent Kinases
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Joonsung Hwang, Long He, Raymond L. Erikson, Xinmin Zhou, Yifeng Yang, Kyoon Eon Kim, Zunnan Huang, Bo Yeon Kim, In Ja Ryoo, Jae-Hyuk Jang, Nak Kyun Soung, Ann M. Bode, Jong Seog Ahn, Kangdong Liu, Zigang Dong, Chan Mi Park, Haidan Liu, Sun Ok Kim, Naomi Oi, Ki Won Lee, and N. R. Thimmegowda
- Subjects
Models, Molecular ,Skin Neoplasms ,Allosteric regulation ,Mice, Nude ,Biology ,Crystallography, X-Ray ,Retinoblastoma Protein ,Biochemistry ,S Phase ,Mice ,chemistry.chemical_compound ,Allosteric Regulation ,Cyclin-dependent kinase ,Cell Line, Tumor ,Animals ,Humans ,Neoplastic transformation ,Chrysin ,Protein Kinase Inhibitors ,Molecular Biology ,Flavonoids ,Mice, Inbred BALB C ,Binding Sites ,Epidermal Growth Factor ,Kinase ,Cyclin-dependent kinase 2 ,G1 Phase ,Retinoblastoma protein ,Cell Biology ,Cyclin-Dependent Kinases ,chemistry ,Epidermoid carcinoma ,Carcinoma, Squamous Cell ,biology.protein ,Neoplasm Transplantation - Abstract
Chrysin (5,7-dihydroxyflavone), a natural flavonoid widely distributed in plants, reportedly has chemopreventive properties against various cancers. However, the anticancer activity of chrysin observed in in vivo studies has been disappointing. Here, we report that a chrysin derivative, referred to as compound 69407, more strongly inhibited EGF-induced neoplastic transformation of JB6 P+ cells compared with chrysin. It attenuated cell cycle progression of EGF-stimulated cells at the G1 phase and inhibited the G1/S transition. It caused loss of retinoblastoma phosphorylation at both Ser-795 and Ser-807/811, the preferred sites phosphorylated by Cdk4/6 and Cdk2, respectively. It also suppressed anchorage-dependent and -independent growth of A431 human epidermoid carcinoma cells. Compound 69407 reduced tumor growth in the A431 mouse xenograft model and retinoblastoma phosphorylation at Ser-795 and Ser-807/811. Immunoprecipitation kinase assay results showed that compound 69407 attenuated endogenous Cdk4 and Cdk2 kinase activities in EGF-stimulated JB6 P+ cells. Pulldown and in vitro kinase assay results indicated that compound 69407 directly binds with Cdk2 and Cdk4 in an ATP-independent manner and inhibited their kinase activities. A binding model between compound 69407 and a crystal structure of Cdk2 predicted that compound 69407 was located inside the Cdk2 allosteric binding site. The binding was further verified by a point mutation binding assay. Overall results indicated that compound 69407 is an ATP-noncompetitive cyclin-dependent kinase inhibitor with anti-tumor effects, which acts by binding inside the Cdk2 allosteric pocket. This study provides new insights for creating a general pharmacophore model to design and develop novel ATP-noncompetitive agents with chemopreventive or chemotherapeutic potency. Background: Binding to the ATP site results in poor selectivity; therefore, development of ATP-noncompetitive inhibitors is needed. Results: A modified chrysin with anticancer activity targets Cdks and binds to a Cdk2 allosteric site, not the ATP pocket. Conclusion: Modified chrysin is a novel ATP-noncompetitive inhibitor. Significance: This pharmacophore model might provide insights for the development of new ATP-noncompetitive agents.
- Published
- 2013
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