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Yan HP, Zhao HY, Qiu AC, Chen XC, Chen K, Chen ZL, Yang SF. Real world study on efficacy and safety of surufatinib in advanced solid tumors evaluation. Sci Rep 2025; 15:16294. [PMID: 40348748 PMCID: PMC12065879 DOI: 10.1038/s41598-025-00974-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 05/02/2025] [Indexed: 05/14/2025] Open
Abstract
Surufatinib is a novel, China-developed small-molecule tyrosine kinase inhibitor that demonstrates high selectivity for VEGFR, FGFR1, and CSF1R. Surufatinib has been approved for the treatment of neuroendcrine tumors, including pancreatic neuroendocrine tumors (PNEN) and non-pancreatic neuroendocrine tumors (N-pNEN). The purpose of this retrospective study is to assess Surufatinib's safety and effectiveness in patients with various advanced solid malignancies. The general clinical statistics and follow-up data of patients treated with Surufatinib for advanced solid tumors at Zhejiang Provincial People's Hospital between January 2021 and April 2024 were gathered. Enhanced CT was used to assess the effectiveness during that time, and cases side effects were gathered. Survival rates of different diseases were analyzed using the Kaplan-Meier method. A total of 28 eligible patients were enrolled in this study. At the end of follow-up, treatment with Surufatinib resulted in the following outcomes: Complete response (CR) in 0 cases (0.0%), Partial response (PR) in 5 cases (17.9%), Stable disease (SD) in 7 cases (25.0%), and Progressive disease (PD) in 16 cases (57.1%). Objective response rate (ORR) and Disease control rate (DCR) were 17.9% and 42.9%, respectively. In the PNEN group, ORR was 33.3%, DCR was 66.7%, median progression-free survival (mPFS) was 11 months, while median overall survival (mOS) was 17 months. In the N-pNEN group, ORR was 14.3%, DCR was 42.3%, mPFS was 6 months and mOS was 7 months. ORR was 8.3%, DCR was 25%, mPFS was 2 months, and mOS was 2 months. The most common adverse reactions included hypoproteinemia, proteinuria, bone marrow suppression and gastrointestinal toxicity, and which of them were grade 1 to grade 2. In advanced solid tumors beyond PNEN, Surufatinib demonstrates clinically meaningful survival benefits for patients refractory to standard therapies, with a generally manageable safety profile.
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Affiliation(s)
- Hui-Ping Yan
- Department of Medical Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Hong-Yang Zhao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - An-Chen Qiu
- Department of Medical Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Xiao-Chen Chen
- Department of Medical Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Ke Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Zhe-Ling Chen
- Department of Medical Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
| | - Si-Fu Yang
- Department of Medical Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
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Chen D, Chen J, Xia H, Chen X, Hu J, Wu G, Xu X. Development of a UPLC-MS/MS method for the determination of sulfatinib and its no interaction with myricetin in rats. Front Pharmacol 2024; 15:1498339. [PMID: 39697549 PMCID: PMC11653107 DOI: 10.3389/fphar.2024.1498339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/15/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Sulfatinib is a novel oral tyrosine kinase inhibitor (TKI) with selective inhibition of fibroblast growth factor (FGFR), colony-stimulating factor 1 receptor (CSF-1R) and vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. It has been approved for the therapy of neuroendocrine tumors arising in the non-pancreatic (December 2020) and pancreatic (June 2021) glands. Until now, there has no research on the determination of sulfatinib in biological medium by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Methods The current study validated a sensitive and reliable quantitative detection of sulfatinib in plasma using UPLC-MS/MS for the first time, and investigated the interaction with myricetin in rats. Acetonitrile was used to precipitate the plasma protein, and lenvatinib was employed as the internal standard (IS). Results The method demonstrated that sulfatinib presented high linearity over the concentration of 11-2,000 ng/mL with the lower limit of quantification (LLOQ) of 1 ng/mL. It was validated methodologically that the precision, matrix effect, stability, accuracy and extraction recovery were all within the allowable values. Moreover, male Sprague-Dawley (SD) rats were assigned randomly to assess the interaction between sulfatinib (30 mg/kg) and myricetin (50 mg/kg). Nevertheless, no significant differences of the main pharmacokinetic parameters were revealed. This may be due to insufficient doses of myricetin, or failure of myricetin to act in a timely manner in vivo. Discussion The findings contributed to a better understanding of the metabolism and drug-drug interaction of sulfatinib, but the presence or absence of interactions needs to be confirmed by further studies.
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Affiliation(s)
- Dongxin Chen
- The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Jie Chen
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hailun Xia
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaohai Chen
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jinyu Hu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guangliang Wu
- The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Xuegu Xu
- The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Nickle A, Ko S, Merrill AE. Fibroblast growth factor 2. Differentiation 2024; 139:100733. [PMID: 37858405 PMCID: PMC11009566 DOI: 10.1016/j.diff.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/20/2023] [Accepted: 10/05/2023] [Indexed: 10/21/2023]
Abstract
Fibroblast Growth Factor 2 (FGF2), also known as basic fibroblast growth factor, is a potent stimulator of growth and differentiation in multiple tissues. Its discovery traces back over 50 years ago when it was first isolated from bovine pituitary extracts due to its ability to stimulate fibroblast proliferation. Subsequent studies investigating the genomic structure of FGF2 identified multiple protein isoforms, categorized as the low molecular weight and high molecular weight FGF2. These isoforms arise from alternative translation initiation events and exhibit unique molecular and cellular functions. In this concise review, we aim to provide an overview of what is currently known about the structure, expression, and functions of the FGF2 isoforms within the contexts of development, homeostasis, and disease.
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Affiliation(s)
- Audrey Nickle
- Center for Craniofacial Molecular Biology, Department of Biomedical Sciences, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, 90033, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Sebastian Ko
- Center for Craniofacial Molecular Biology, Department of Biomedical Sciences, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, 90033, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Amy E Merrill
- Center for Craniofacial Molecular Biology, Department of Biomedical Sciences, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, 90033, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
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De Palma M, Hanahan D. Milestones in tumor vascularization and its therapeutic targeting. NATURE CANCER 2024; 5:827-843. [PMID: 38918437 DOI: 10.1038/s43018-024-00780-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 04/22/2024] [Indexed: 06/27/2024]
Abstract
Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future.
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Affiliation(s)
- Michele De Palma
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
| | - Douglas Hanahan
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
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Lin Q, Dai S, Qu L, Lin H, Guo M, Wei H, Chen Y, Chen X. Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R. Commun Chem 2024; 7:3. [PMID: 38172256 PMCID: PMC10764862 DOI: 10.1038/s42004-023-01084-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 12/06/2023] [Indexed: 01/05/2024] Open
Abstract
Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1RT663I. This study not only sheds light on the structural basis governing sulfatinib's FGFR/CSF-1R inhibition, but also provides valuable insights into the rational design of dual- or multi-target FGFR inhibitors with selectivity for CSF-1R and sensitivity to gatekeeper mutations.
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Affiliation(s)
- Qianmeng Lin
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Shuyan Dai
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Lingzhi Qu
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hang Lin
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ming Guo
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hudie Wei
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Xiaojuan Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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Zhi Y, Cai C, Xu T, Sun F, Wang KP, Ji Z, Pei Y, Geng S, Wang H. Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways. J Biochem Mol Toxicol 2023; 37:e23399. [PMID: 37345681 DOI: 10.1002/jbt.23399] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 04/12/2023] [Accepted: 06/08/2023] [Indexed: 06/23/2023]
Abstract
Metabolic abnormalities and uncontrolled angiogenesis are two vital features of malignant tumors. Although fibroblast growth factor 6 (FGF6) is known to promote the proliferation and migration of bladder cancer (BC) cells, its influences on aerobic glycolysis and angiogenesis in BC remain unclear. Gene expression at messenger RNA and protein levels were examined by reverse transcription-quantitative polymerase chain reaction and Western blot analyses, respectively. Lactate production and glucose uptake in BC cells were evaluated by performing aerobic glycolysis assays. A vasculogenic mimicry assay was executed for assessing the angiogenesis of BC cells. The viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) cocultured with supernatants of BC cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound healing assay, and tube formation assay. It was found that FGF6 displayed a high level in BC cell lines. Silencing of FGF6 reduced the levels of lactate production, glucose uptake, and the expression of angiogenic factors and glycolytic enzymes in BC cells, which also inhibited the viability and migration of HUVECs. In addition, FGF6 depletion or aerobic glycolysis inhibitor 2-deoxy-d-glucose treatment decreased the total branching length and intersection number of both BC cells and HUVECs. Moreover, glucose or lactate treatment reversed FGF6-induced suppression of cell viability, migration, tube formation, and vasculogenic mimicry. The activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways was blocked by silenced FGF6. Furthermore, PI3K/Akt inhibitor (LY2940002) and p38-MAPK inhibitor (SB203580) inhibited the levels of aerobic glycolysis-related proteins. In conclusion, FGF6 knockdown suppressed aerobic glycolysis, thereby inhibiting angiogenesis in BC via regulation of the PI3K/Akt and MAPK signaling pathways.
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Affiliation(s)
- Yunlai Zhi
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Chengkuan Cai
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Tianxi Xu
- Department of Basic Medicine, Shandong University, Grade 2021, Jinan, Shandong, China
| | - Fanghu Sun
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Kun Peng Wang
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Zhengshuai Ji
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Yuhan Pei
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Shen Geng
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Hui Wang
- Department of Urology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
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7
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Abouelnazar FA, Zhang X, Zhang J, Wang M, Yu D, Zang X, Zhang J, Li Y, Xu J, Yang Q, Zhou Y, Tang H, Wang Y, Gu J, Zhang X. SALL4 promotes angiogenesis in gastric cancer by regulating VEGF expression and targeting SALL4/VEGF pathway inhibits cancer progression. Cancer Cell Int 2023; 23:149. [PMID: 37525212 PMCID: PMC10388482 DOI: 10.1186/s12935-023-02985-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 07/04/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Spalt-like protein 4 (SALL4) is a stemness-related transcription factor whose abnormal re-expression contributes to cancer initiation and progression. However, the role of SALL4 in cancer angiogenesis remains unknown. METHODS Analyses of clinical specimens via TCGA datasets were performed to determine the expression level and clinical significance of SALL4 in STAD (Stomach Adenocarcinoma). SALL4 knockdown, knockout, and overexpression were achieved by siRNA, CRISPR/Cas9, and plasmid transfection. The effects of conditioned medium (CM) from SALL4 knockdown or overexpression of gastric cancer cells on endothelial cell proliferation, migration, and tube formation were investigated by CCK-8 assay, transwell migration assay, and tube formation assay. The regulation of VEGF gene expression by SALL4 was studied by qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assay, and electrophoretic mobility shift assay (EMSA). Engineered exosomes from 293T cells loaded with si-SALL4-B and thalidomide were produced to test their therapeutic effect on gastric cancer progression. RESULTS SALL4 expression was increased in STAD and positively correlated with tumor progression and poor prognosis. SALL4-B knockdown or knockout decreased while over-expression increased the promotion of human umbilical vein endothelial cells (HUVEC) cell proliferation, migration, and tube formation by gastric cancer cell-derived CM. Further investigation revealed a widespread association of SALL4 with angiogenic gene transcription through the TCGA datasets. Additionally, SALL4-B knockdown reduced, while over-expression enhanced the expression levels of VEGF-A, B, and C genes. The results of ChIP and EMSA assays indicated that SALL4 could directly bind to the promoters of VEGF-A, B, and C genes and activate their transcription, which may be associated with increased histone H3-K79 and H3-K4 modifications in their promoter regions. Furthermore, si-SALL4-B and thalidomide-loaded exosomes could be efficiently uptaken by gastric cancer cells and significantly reduced SALL4-B and Vascular Endothelial Growth Factor (VEGF) expression levels in gastric cancer cells, thus inhibiting the pro-angiogenic role of their derived CM. CONCLUSION These findings suggest that SALL4 plays an important role in angiogenesis by transcriptionally regulating VEGF expression. Co-delivery of the functional siRNA and anticancer drug via exosomes represents a useful approach to inhibiting cancer angiogenesis by targeting SALL4/VEGF pathway.
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Grants
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (2019GSZDSYS01, 2019GSZDSYS02) Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical On-cology in Gansu Province
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (NLDTG2020002) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (JC2021092) Nantong Science and Technology Bureau Project
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
- (KYCX21_3405, KYCX22_3713) Postgraduate Research & Practice Innovation Program of Jiangsu Province
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Affiliation(s)
- Fatma A Abouelnazar
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Xiaoxin Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Jiahui Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Maoye Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Dan Yu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Xueyan Zang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Jiayin Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Yixin Li
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Jing Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Qiurong Yang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Yue Zhou
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Haozhou Tang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Yanzheng Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Jianmei Gu
- Department of Clinical Laboratory Medicine, Affiliated Cancer Hospital of Nantong University, Nantong, 226300, China.
| | - Xu Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
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Bhardwaj V, Zhang X, Pandey V, Garg M. Neo-vascularization-based therapeutic perspectives in advanced ovarian cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188888. [PMID: 37001618 DOI: 10.1016/j.bbcan.2023.188888] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/23/2023] [Accepted: 03/02/2023] [Indexed: 03/30/2023]
Abstract
The process of angiogenesis is well described for its potential role in the development of normal ovaries, and physiological functions as well as in the initiation, progression, and metastasis of ovarian cancer (OC). In advanced stages of OC, cancer cells spread outside the ovary to the pelvic, abdomen, lung, or multiple secondary sites. This seriously limits the efficacy of therapeutic options contributing to fatal clinical outcomes. Notably, a variety of angiogenic effectors are produced by the tumor cells to initiate angiogenic processes leading to the development of new blood vessels, which provide essential resources for tumor survival, dissemination, and dormant micro-metastasis of tumor cells. Multiple proangiogenic effectors and their signaling axis have been discovered and functionally characterized for potential clinical utility in OC. In this review, we have provided the current updates on classical and emerging proangiogenic effectors, their signaling axis, and the immune microenvironment contributing to the pathogenesis of OC. Moreover, we have comprehensively reviewed and discussed the significance of the preclinical strategies, drug repurposing, and clinical trials targeting the angiogenic processes that hold promising perspectives for the better management of patients with OC.
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Affiliation(s)
- Vipul Bhardwaj
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Institute of Biopharmaceutical and Bioengineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China
| | - Xi Zhang
- Shenzhen Bay Laboratory, Shenzhen 518055, PR China
| | - Vijay Pandey
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Institute of Biopharmaceutical and Bioengineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Sector-125, Noida 201301, India.
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9
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Nakamura T, Hashita T, Chen Y, Gao Y, Sun Y, Islam S, Sato H, Shibuya Y, Zou K, Matsunaga T, Michikawa M. Aβ42 treatment of the brain side reduced the level of flotillin from endothelial cells on the blood side via FGF-2 signaling in a blood-brain barrier model. Mol Brain 2023; 16:15. [PMID: 36698209 PMCID: PMC9878866 DOI: 10.1186/s13041-023-01005-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 01/13/2023] [Indexed: 01/27/2023] Open
Abstract
Our previous study showed that the flotillin level is decreased in the blood of patients with Alzheimer's disease (AD) when compared to that of patients with non-AD and vascular dementia; however, the molecular mechanism remains to be determined. In this study, to elucidate whether Aβ accumulation in the brain has an effect on the blood flotillin level, we used our previously established blood-brain barrier (BBB) culture model using microvascular endothelial cells obtained from human induced pluripotent stem cells (iBMECs) and astrocytes prepared from rat cortex. In this BBB model with iBMECs plated on the upper compartment (blood side) and astrocytes plated on the lower compartment (brain side), the trans-endothelial electrical resistance values are high (over 1500 Ωm2) and stable during experiments. We found that the addition of Aβ42 (0.5 and 2 µM) to the brain side significantly reduced the level of flotillin secreted by iBMECs on the blood side. The level of basic fibroblast growth factor (FGF-2) in the brain side was significantly reduced by Aβ42 treatment, and was accompanied by a reduction in the level of phosphorylation of the fibroblast growth factor receptor in iBMECs. The brain-side Aβ42 treatment-induced reduction of flotillin secretion into the blood side was restored in a dose-dependent manner by the addition of FGF-2 into the brain side. These results indicated that Aβ accumulation in the brain side reduced FGF-2 release from astrocytes, which attenuated FGF-2-mediated iBMECs signaling via the FGF-2 receptor, and thereby reduced flotillin secretion from iBMECs on the blood side. Our findings revealed a novel signaling pathway crossing the BBB from the brain side to the blood side, which is different from the classical intramural periarterial drainage or lymphatic-system-to-blood pathway.
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Affiliation(s)
- Tomohisa Nakamura
- grid.260433.00000 0001 0728 1069Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan ,grid.260433.00000 0001 0728 1069Department of Maxillofacial Surgery, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
| | - Tadahiro Hashita
- grid.260433.00000 0001 0728 1069Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-Ku, Nagoya, 467-8603 Japan
| | - Yuxin Chen
- grid.260433.00000 0001 0728 1069Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
| | - Yuan Gao
- grid.260433.00000 0001 0728 1069Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
| | - Yang Sun
- grid.260433.00000 0001 0728 1069Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
| | - Sadequl Islam
- grid.260433.00000 0001 0728 1069Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
| | - Hiroyuki Sato
- grid.260433.00000 0001 0728 1069Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-Ku, Nagoya, 467-8603 Japan
| | - Yasuyuki Shibuya
- grid.260433.00000 0001 0728 1069Department of Maxillofacial Surgery, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
| | - Kun Zou
- grid.260433.00000 0001 0728 1069Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
| | - Tamihide Matsunaga
- grid.260433.00000 0001 0728 1069Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-Ku, Nagoya, 467-8603 Japan
| | - Makoto Michikawa
- grid.260433.00000 0001 0728 1069Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, Nagoya, 467-8601 Japan
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10
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TNFAIP3 mediates FGFR1 activation-induced breast cancer angiogenesis by promoting VEGFA expression and secretion. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2453-2465. [PMID: 36002765 DOI: 10.1007/s12094-022-02918-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/30/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE To investigate the role and mechanism of TNF-inducible protein 3(TNFAIP3) in breast cancer angiogenesis induced by fibroblast growth factor receptor1 (FGFR1) activation. METHODS The immunohistochemical assay was used to detect the expression of vascular endothelial cell marker CD31 and CD105 in mice DCIS.COM-iFGFR1 transplanted tumor (previously established by our group). The effects of TNFAIP3 knockout/knockdown breast cancer cell lines on angiogenesis, migration, and invasion of Human Umbilical Vein Endothelial Cells (HUVEC) were detected by the tubulogenesis and Trewells assay. RNA-seq analysis of TNFAIP3 downstreams differential genes after TNFAIP3 knockdown. The expression and secretion of VEGFA after FGFR1 activation in breast cancer cells were detected by qPCR, Western blot, and ELISA. RESULTS Immunohistochemistry showed that TNFAIP3 knockout inhibited the expression of CD31 and CD105 in DCIS grafted tumors promoted by FGFR1 activation. Tubulogenesis and Trewells experiments showed that TNFAIP3 gene knockout/knockdown inhibited the angiogenesis, migration, and invasion of HUVEC cells promoted by FGFR1 activation. qPCR assay showed that VEGFA mRNA level in the TNFAIP3 knockdown cell line was significantly down-regulated (p < 0.05). qPCR, Western blot and ELISA results showed that TNFAIP3 gene knockout/knockdown could inhibit the expression and secretion of VEGFA in breast cancer cells induced by FGFR1 activation. CONCLUSION TNFAIP3 promotes breast cancer angiogenesis induced by FGFR1 activation through the expression and secretion of VEGFA.
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11
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VEGF-A and FGF4 Engineered C2C12 Myoblasts and Angiogenesis in the Chick Chorioallantoic Membrane. Biomedicines 2022; 10:biomedicines10081781. [PMID: 35892681 PMCID: PMC9330725 DOI: 10.3390/biomedicines10081781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/06/2022] [Accepted: 07/21/2022] [Indexed: 01/04/2023] Open
Abstract
Angiogenesis is the formation of new blood vessels from pre-existing vessels. Adequate oxygen transport and waste removal are necessary for tissue homeostasis. Restrictions in blood supply can lead to ischaemia which can contribute to disease pathology. Vascular endothelial growth factor (VEGF) is essential in angiogenesis and myogenesis, making it an ideal candidate for angiogenic and myogenic stimulation in muscle. We established C2C12 mouse myoblast cell lines which stably express elevated levels of (i) human VEGF-A and (ii) dual human FGF4-VEGF-A. Both stably transfected cells secreted increased amounts of human VEGF-A compared to non-transfected cells, with the latter greater than the former. In vitro, conditioned media from engineered cells resulted in a significant increase in endothelial cell proliferation, migration, and tube formation. In vivo, this conditioned media produced a 1.5-fold increase in angiogenesis in the chick chorioallantoic membrane (CAM) assay. Delivery of the engineered myoblasts on Matrigel demonstrated continued biological activity by eliciting an almost 2-fold increase in angiogenic response when applied directly to the CAM assay. These studies qualify the use of genetically modified myoblasts in therapeutic angiogenesis for the treatment of muscle diseases associated with vascular defects.
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12
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Hsu MJ, Chen HK, Lien JC, Huang YH, Huang SW. Suppressing VEGF-A/VEGFR-2 Signaling Contributes to the Anti-Angiogenic Effects of PPE8, a Novel Naphthoquinone-Based Compound. Cells 2022; 11:cells11132114. [PMID: 35805198 PMCID: PMC9266117 DOI: 10.3390/cells11132114] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/30/2022] [Accepted: 07/02/2022] [Indexed: 02/05/2023] Open
Abstract
Natural naphthoquinones and their derivatives exhibit a broad spectrum of pharmacological activities and have thus attracted much attention in modern drug discovery. However, it remains unclear whether naphthoquinones are potential drug candidates for anti-angiogenic agents. The aim of this study was to evaluate the anti-angiogenic properties of a novel naphthoquinone derivative, PPE8, and explore its underlying mechanisms. Determined by various assays including BrdU, migration, invasion, and tube formation analyses, PPE8 treatment resulted in the reduction of VEGF-A-induced proliferation, migration, and invasion, as well as tube formation in human umbilical vein endothelial cells (HUVECs). We also used an aorta ring sprouting assay, Matrigel plug assay, and immunoblotting analysis to examine PPE8’s ex vivo and in vivo anti-angiogenic activities and its actions on VEGF-A signaling. It has been revealed that PPE8 inhibited VEGF-A-induced micro vessel sprouting and was capable of suppressing angiogenesis in in vivo models. In addition, PPE8 inhibited VEGF receptor (VEGFR)-2, Src, FAK, ERK1/2, or AKT phosphorylation in HUVECs exposed to VEGF-A, and it also showed significant decline in xenograft tumor growth in vivo. Taken together, these observations indicated that PPE8 may target VEGF-A–VEGFR-2 signaling to reduce angiogenesis. It also supports the role of PPE8 as a potential drug candidate for the development of therapeutic agents in the treatment of angiogenesis-related diseases including cancer.
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Affiliation(s)
- Ming-Jen Hsu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Han-Kun Chen
- Department of General Surgery, Chi Mei Medical Center, Tainan 71067, Taiwan;
| | - Jin-Cherng Lien
- School of Pharmacy, China Medical University, Taichung 40402, Taiwan;
- Department of Medical Research, Hospital of China Medical University, Taichung 40402, Taiwan
| | - Yu-Han Huang
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
- The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Shiu-Wen Huang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Medical Research, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Research Center of Thoracic Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Correspondence: ; Tel.: +886-2-27361661 (ext. 3198)
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Yao X, Qi G, Qu Y, Yun S, Sun W, Liang C, Du M, Li Z. Structural Characterization of RC28-E, a Recombinant Fusion Protein With Dual Targets on VEGF and FGF2. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221086989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) and fibroblast growthfactor (FGF) play important roles in angiogenesis-related diseases. RC28-E is a soluble fusion protein composed of the human VEGF receptor 1 (VEGFR1) extracellular domain 2 (ECD 2), VEGFR2 ECD 3, FGFR1 ECDs 2 and 3, and the Fc regions of human immunoglobulin G1. By targeting both VEGF and FGF2, RC28-E may represent a useful antiangiogenetic agent, but structural and functional characterizations of this fusion protein are needed. Liquid chromatography–tandem mass spectrometry, size exclusion high-performance liquid chromatography, capillary electrophoresis-sodium dodecyl sulfate, imaged capillary isoelectric focusing, and bio-layer interferometry were used to characterize the properties of RC28-E. The purity of RC28-E was confirmed to be 98% or greater. The glycosylation modification of RC28-E was found to be very complicated, with 11 potential N-linked glycosylation points and 23 types of N-glycans, causing high heterogeneity of the protein. The primary modifications of the amino acid sequence of RC28-E protein included C-terminal K truncation, N-deamidation, and M-oxidation modification. Notably, RC28-E demonstrated a higher affinity for both VEGF and FGF2 than VEGF trap or FGF trap for their respective targets.
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Affiliation(s)
| | - Guiping Qi
- RemeGen Co., Ltd, Yantai, Shandong, China
| | | | - Shasha Yun
- RemeGen Co., Ltd, Yantai, Shandong, China
| | | | | | - Mupeng Du
- RemeGen Co., Ltd, Yantai, Shandong, China
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14
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Pradubyat N, Giannoudis A, Elmetwali T, Mahalapbutr P, Palmieri C, Mitrpant C, Ketchart W. 1'-Acetoxychavicol Acetate from Alpinia galanga Represses Proliferation and Invasion, and Induces Apoptosis via HER2-signaling in Endocrine-Resistant Breast Cancer Cells. PLANTA MEDICA 2022; 88:163-178. [PMID: 33445186 DOI: 10.1055/a-1307-3997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Estrogen receptor-positive breast cancer patients have a good prognosis, but 30% of these patients will experience recurrence due to the development of resistance through various signaling pathways. This study aimed to evaluate the mode of anticancer effects of 1'-acetoxychavicol acetate, which is isolated from the rhizomes of Alpinia galanga in estrogen receptor positive (MCF7) human epidermal growth factor receptor 2-overexpressed (MCF7/HER2), and endocrine-resistant breast cancer cells (MCF7/LCC2 and MCF7/LCC9). 1'-Acetoxychavicol acetate showed antiproliferation in a concentration- and time-dependent fashion and had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines. This was associated with down-regulation of human epidermal growth factor receptor 2, pERK1/2, pAKT, estrogen receptor coactivator, cyclin D1, and MYC proto-oncogene while in vivo and significant reduction in the tumor mass of 1'-acetoxychavicol acetate-treated zebrafish-engrafted breast cancer groups. The anti-invasive effects of 1'-acetoxychavicol acetate were confirmed in vitro by the matrigel invasion assay and with down-regulation of C - X-C chemokine receptor type 4, urokinase plasminogen activator, vascular endothelial growth factor, and basic fibroblast growth factor 2 genes. The down-regulation of urokinase plasminogen activator and fibroblast growth factor 2 proteins was also validated by molecular docking analysis. Moreover, 1'-acetoxychavicol acetate-treated cells exhibited lower expression levels of the anti-apoptotic Bcl-2 and Mcl-1 proteins in addition to enhanced stress-activated kinases/c-Jun N-terminal kinase 1/2 and poly-ADP ribose polymerase cleavage, indicating apoptotic cell induction by 1'-acetoxychavicol acetate. Moreover, 1'-acetoxychavicol acetate had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines regarding its inhibition on human epidermal growth factor receptor 2, pAKT, pERK1/2, PSer118, and PSer167-ERα proteins. Our findings suggest 1'-acetoxychavicol acetate mediates its anti-cancer effects via human epidermal growth factor receptor 2 signaling pathway.
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Affiliation(s)
- Nalinee Pradubyat
- Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
- Overcoming cancer drug resistance research unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Athina Giannoudis
- Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
| | - Taha Elmetwali
- Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
| | - Panupong Mahalapbutr
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Carlo Palmieri
- Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
- Clatterbridge Cancer Centre, NHS Foundation Trust, Liverpool, United Kingdom of Great Britain
| | - Chalermchai Mitrpant
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Perron Institute for Neurological and Translational Science, Perth, Nedlands, Perth, Western Australia, Australia
| | - Wannarasmi Ketchart
- Overcoming cancer drug resistance research unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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15
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Santorelli S, Fischer DP, Harte MK, Laru J, Marshall KM. In vivo effects of AZD4547, a novel fibroblast growth factor receptor inhibitor, in a mouse model of endometriosis. Pharmacol Res Perspect 2021; 9:e00759. [PMID: 33811484 PMCID: PMC8019068 DOI: 10.1002/prp2.759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 11/22/2020] [Indexed: 11/12/2022] Open
Abstract
Endometriosis is a chronic disease, characterized by the growth of endometrial-like cells outside the uterine cavity. Due to its complex pathophysiology, a totally resolving cure is yet to be found. The aim of this study was to compare the therapeutic efficacy of AZD4547, a novel fibroblast growth factor receptor inhibitor (FGFRI), with a well-characterized progestin, etonogestrel (ENG) using a validated in vivo mouse model of endometriosis. Endometriosis was induced by transplanting uterine fragments from donor mice in proestrus into the peritoneal cavity of recipient mice, which then developed into cyst-like lesions. AZD4547 and ENG were administered systemically either from the day of endometriosis induction or 2-weeks post-surgery. After 20 days of treatment, the lesions were harvested; their size and weight were measured and analyzed histologically or by qRT-PCR. Stage of estrous cycle was monitored throughout. Compared to vehicle, AZD4547 (25 mg/kg) was most effective in counteracting lesion growth when treating from day of surgery and 2 weeks after; ENG (0.8 mg/kg) was similarly effective in reducing lesion growth but only when administered from day of surgery. Each downregulated FGFR gene expression (p < 0.05). AZD4547 at all doses and ENG (0.008 mg/kg) caused no disturbance to the estrous cycle. ENG at 0.08 and 0.8 mg/kg was associated with partial or complete estrous cycle disruption and hyperemia of the uteri. AZD4547 and ENG both attenuated endometriotic lesion size, but only AZD4547 did not disrupt the estrous cycle, suggesting that targeting of FGFR is worthy of further investigation as a novel treatment for endometriosis.
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Affiliation(s)
- Sara Santorelli
- NorthWest Centre for Advanced Drug Delivery (NoWCADD), School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,AstraZeneca, Cambridge, UK
| | - Deborah P Fischer
- NorthWest Centre for Advanced Drug Delivery (NoWCADD), School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Michael K Harte
- Division of Pharmacy and Optometry, University of Manchester, Manchester, UK
| | - Johanna Laru
- Early Product Development, Pharmaceutical Sciences, iMED Biotech Unit, AstraZeneca, Macclesfield, UK
| | - Kay M Marshall
- NorthWest Centre for Advanced Drug Delivery (NoWCADD), School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
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16
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Zahra FT, Sajib MS, Mikelis CM. Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer. Cancers (Basel) 2021; 13:1422. [PMID: 33804681 PMCID: PMC8003808 DOI: 10.3390/cancers13061422] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Anti-angiogenic approaches targeting the vascular endothelial growth factor (VEGF) signaling pathway have been a significant research focus during the past decades and are well established in clinical practice. Despite the expectations, their benefit is ephemeral in several diseases, including specific cancers. One of the most prominent side effects of the current, VEGF-based, anti-angiogenic treatments remains the development of resistance, mostly due to the upregulation and compensatory mechanisms of other growth factors, with the basic fibroblast growth factor (bFGF) being at the top of the list. Over the past decade, several anti-angiogenic approaches targeting simultaneously different growth factors and their signaling pathways have been developed and some have reached the clinical practice. In the present review, we summarize the knowledge regarding resistance mechanisms upon anti-angiogenic treatment, mainly focusing on bFGF. We discuss its role in acquired resistance upon prolonged anti-angiogenic treatment in different tumor settings, outline the reported resistance mechanisms leading to bFGF upregulation, and summarize the efforts and outcome of combined anti-angiogenic approaches to date.
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Affiliation(s)
| | | | - Constantinos M. Mikelis
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (F.T.Z.); (M.S.S.)
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17
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Sobhani N, Fassl A, Mondani G, Generali D, Otto T. Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer. Cells 2021; 10:293. [PMID: 33535617 PMCID: PMC7912842 DOI: 10.3390/cells10020293] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/26/2021] [Accepted: 01/29/2021] [Indexed: 01/01/2023] Open
Abstract
Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)-in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.
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Affiliation(s)
- Navid Sobhani
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX 77030, USA
| | - Anne Fassl
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Giuseppina Mondani
- Department Breast Oncoplastic Surgery Royal Cornwall Hospital, Treliske, Truro TR13LJ, UK;
| | - Daniele Generali
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, 34149 Trieste, Italy;
| | - Tobias Otto
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
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Pradhan AK, Maji S, Das SK, Emdad L, Sarkar D, Fisher PB. MDA-9/Syntenin/SDCBP: new insights into a unique multifunctional scaffold protein. Cancer Metastasis Rev 2021; 39:769-781. [PMID: 32410111 DOI: 10.1007/s10555-020-09886-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor metastasis comprises a series of coordinated events that culminate in dissemination of cancer cells to distant sites within the body representing the greatest challenge impeding effective therapy of cancer and the leading cause of cancer-associated morbidity. Cancer cells exploit multiple genes and pathways to colonize to distant organs. These pathways are integrated and regulated at different levels by cellular- and extracellular-associated factors. Defining the genes and pathways that govern metastasis can provide new targets for therapeutic intervention. Melanoma differentiation associated gene-9 (mda-9) (also known as Syntenin-1 and SDCBP (Syndecan binding protein)) was identified by subtraction hybridization as a novel gene displaying differential temporal expression during differentiation of melanoma. MDA-9/Syntenin is an established Syndecan binding protein that functions as an adaptor protein. Expression of MDA-9/Syntenin is elevated at an RNA and protein level in a wide-range of cancers including melanoma, glioblastoma, neuroblastoma, and prostate, breast and liver cancer. Expression is increased significantly in metastatic cancer cells as compared with non-metastatic cancer cells or normal cells, which make it an attractive target in treating cancer metastasis. In this review, we focus on the role and regulation of mda-9 in cancer progression and metastasis.
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Affiliation(s)
- Anjan K Pradhan
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA
| | - Santanu Maji
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA. .,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA. .,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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Recent advances of dual FGFR inhibitors as a novel therapy for cancer. Eur J Med Chem 2021; 214:113205. [PMID: 33556787 DOI: 10.1016/j.ejmech.2021.113205] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/06/2021] [Accepted: 01/13/2021] [Indexed: 12/14/2022]
Abstract
Fibroblast growth factor receptor (FGFR) includes four highly conserved transmembrane receptor tyrosine kinases (FGFR1-4). FGF and FGFR regulate many biological processes, such as angiogenesis, wound healing and tissue regeneration. The abnormal expression of FGFR is related to the tumorigenesis, tumor progression and drug resistance of anti-tumor treatments in many types of tumors. Nowadays there are many anti-cancer drugs targeting FGFR. However, traditional single-target anti-tumor drugs are easy to acquire drug resistance. The therapeutic effect can be enhanced by simultaneously inhibiting FGFR and another target (such as VEGFR, EGFR, PI3K, CSF-1R, etc.). We know drug combination can bring problems such as drug interactions. Therefore, the development of FGFR dual target inhibitors is an important direction. In this paper, we reviewed the research on dual FGFR inhibitors in recent years and made brief comments on them.
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Yetkin-Arik B, Kastelein AW, Klaassen I, Jansen CHJR, Latul YP, Vittori M, Biri A, Kahraman K, Griffioen AW, Amant F, Lok CAR, Schlingemann RO, van Noorden CJF. Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy. Biochim Biophys Acta Rev Cancer 2020; 1875:188446. [PMID: 33058997 DOI: 10.1016/j.bbcan.2020.188446] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 10/02/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023]
Abstract
Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.
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Affiliation(s)
- Bahar Yetkin-Arik
- Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Medical Biology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Arnoud W Kastelein
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands.
| | - Ingeborg Klaassen
- Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Medical Biology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Charlotte H J R Jansen
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Yani P Latul
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Miloš Vittori
- Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Aydan Biri
- Department of Obstetrics and Gynecology, Koru Ankara Hospital, Ankara, Turkey
| | - Korhan Kahraman
- Department of Obstetrics and Gynecology, Bahcesehir University School of Medicine, Istanbul, Turkey
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Frederic Amant
- Department of Oncology, KU Leuven, Leuven, Belgium; Center for Gynaecological Oncology, Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Center for Gynaecological Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Center for Gynaecological Oncology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Christianne A R Lok
- Center for Gynaecological Oncology, Antoni van Leeuwenhoek, Amsterdam, the Netherlands
| | - Reinier O Schlingemann
- Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Cornelis J F van Noorden
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
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21
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Yao Y, Liu Z, Zhao M, Chen Z, Li P, Zhang Y, Wang Y, Zhao C, Long C, Chen X, Yang J. Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy. Acta Pharm Sin B 2020; 10:1453-1475. [PMID: 32963943 PMCID: PMC7488503 DOI: 10.1016/j.apsb.2020.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.
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Key Words
- ATCC, American Type Culture Collection
- AUC, area under the plasma concentration–time curve
- Anti-angiogenesis therapy
- CE, collision energy
- CL, systemic clearance
- Cmax, maximum plasma concentration
- Drug synthesis
- EC, vascular endothelial cell
- ECM, endothelial cell medium
- ERKs, extracellular signal-regulated kinases
- FGF, fibroblast growth factor
- FGFRs, fibroblast growth factor receptors
- HBVPs, human brain vascular pericytes
- HUVECs, human umbilical vein endothelial cells
- IC50, half maximal inhibitory concentration
- IHC, immunohistochemistry
- LC–MS, liquid chromatography mass spectrometry
- LLOQ, lower limit of quantification
- MRM, multiple reaction monitoring
- MsOH, methane sulfonic acid
- Multi-angiokinase inhibitor
- NMR, nuclear magnetic resonance
- PD, pharmacodynamics
- PDB, protein data bank
- PDGF, platelet-derived growth factor
- PDGFRs, platelet-derived growth factor receptors
- PDX, patient-derived tumor xenograft
- PK, pharmacokinetics
- PM, pericyte medium
- Pharmacokinetic
- QC, quality control
- RE, values and relative error
- RSD, relative standard deviation
- RTKs, receptor tyrosine kinases
- TGI, tumor growth inhibition rate
- TLC, thin-layer chromatography
- Tmax, time the maximum concentration occurred
- Tumor
- ULOQ, up limit of quantitation
- VEGF, vascular endothelial growth factor
- VEGFRs, vascular endothelial growth factor receptors
- Vdss, volume of distribution at steady state
- i.v., intravenous injection
- p.o., per os
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Affiliation(s)
- Yuqin Yao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
- Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan 523325, China
- West China School of Public Health and West China Fourth Hospital, Healthy Food Evaluation Research Center, Sichuan University, Chengdu 610041, China
| | - Zhuowei Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
- Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan 523325, China
- Guangdong Raynovent Biotech Co., Ltd. Dongguan 523325, China
| | - Manyu Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
- West China School of Public Health and West China Fourth Hospital, Healthy Food Evaluation Research Center, Sichuan University, Chengdu 610041, China
| | | | - Peng Li
- WuXi AppTec Ltd. Shanghai 200131, China
| | | | - Yuxi Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Chengjian Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Chaofeng Long
- Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan 523325, China
- Guangdong Raynovent Biotech Co., Ltd. Dongguan 523325, China
| | - Xiaoxin Chen
- Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan 523325, China
- Guangdong Raynovent Biotech Co., Ltd. Dongguan 523325, China
| | - Jinliang Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
- Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan 523325, China
- West China School of Public Health and West China Fourth Hospital, Healthy Food Evaluation Research Center, Sichuan University, Chengdu 610041, China
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22
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Kisin ER, Yanamala N, Rodin D, Menas A, Farcas M, Russo M, Guppi S, Khaliullin TO, Iavicoli I, Harper M, Star A, Kagan VE, Shvedova AA. Enhanced morphological transformation of human lung epithelial cells by continuous exposure to cellulose nanocrystals. CHEMOSPHERE 2020; 250:126170. [PMID: 32114335 PMCID: PMC7750788 DOI: 10.1016/j.chemosphere.2020.126170] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/30/2020] [Accepted: 02/09/2020] [Indexed: 05/06/2023]
Abstract
Cellulose nanocrystals (CNC), also known as nanowhiskers, have recently gained much attention due to their biodegradable nature, advantageous chemical and mechanical properties, economic value and renewability thus making them attractive for a wide range of applications. However, before these materials can be considered for potential uses, investigation of their toxicity is prudent. Although CNC exposures are associated with pulmonary inflammation and damage as well as oxidative stress responses and genotoxicity in vivo, studies evaluating cell transformation or tumorigenic potential of CNC's were not previously conducted. In this study, we aimed to assess the neoplastic-like transformation potential of two forms of CNC derived from wood (powder and gel) in human pulmonary epithelial cells (BEAS-2B) in comparison to fibrous tremolite (TF), known to induce lung cancer. Short-term exposure to CNC or TF induced intracellular ROS increase and DNA damage while long-term exposure resulted in neoplastic-like transformation demonstrated by increased cell proliferation, anchorage-independent growth, migration and invasion. The increased proliferative responses were also in-agreement with observed levels of pro-inflammatory cytokines. Based on the hierarchical clustering analysis (HCA) of the inflammatory cytokine responses, CNC powder was segregated from the control and CNC-gel samples. This suggests that CNC may have the ability to influence neoplastic-like transformation events in pulmonary epithelial cells and that such effects are dependent on the type/form of CNC. Further studies focusing on determining and understanding molecular mechanisms underlying potential CNC cell transformation events and their likelihood to induce tumorigenic effects in vivo are highly warranted.
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Affiliation(s)
- E R Kisin
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA
| | - N Yanamala
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA
| | - D Rodin
- Institute for Personalized and Translational Medicine, Ariel University, Ariel, Israel
| | - A Menas
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA
| | - M Farcas
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA
| | - M Russo
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA; Institute of Public Health, Section of Occupational Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - S Guppi
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA
| | - T O Khaliullin
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA; Department of Physiology & Pharmacology, WVU, Morgantown, WV, USA
| | - I Iavicoli
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - M Harper
- Zefon International, Ocala, FL, USA
| | - A Star
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA
| | - V E Kagan
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Laboratory of Navigational Redox Lipidomics, IM Sechenov Moscow State Medical University, Moscow, Russian Federation
| | - A A Shvedova
- EAB, HELD, NIOSH, CDC, Morgantown, WV, USA; Department of Physiology & Pharmacology, WVU, Morgantown, WV, USA.
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Inhibition of FGF2-Mediated Signaling in GIST-Promising Approach for Overcoming Resistance to Imatinib. Cancers (Basel) 2020; 12:cancers12061674. [PMID: 32599808 PMCID: PMC7352302 DOI: 10.3390/cancers12061674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/12/2020] [Accepted: 06/18/2020] [Indexed: 12/19/2022] Open
Abstract
Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.
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Abstract
PURPOSE Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXibs) inhibit the progression of endometrial cancer, ovarian cancer and cervical cancer. However, concerning the adverse effects of NSAIDs and COXibs, it is still urgent and necessary to explore novel and specific anti-inflammation targets for potential chemoprevention. The signaling of cyclooxygenase 2-prostaglandin E2-prostaglandin E2 receptors (COX-2-PGE2-EPs) is the central inflammatory pathway involved in the gynecological carcinogenesis. METHODS Literature searches were performed to the function of COX-2-PGE2-EPs in gynecological malignancies. RESULTS This review provides an overview of the current knowledge of COX-2-PGE2-EPs signaling in endometrial cancer, ovarian cancer and cervical cancer. Many studies demonstrated the upregulated expression of the whole signaling pathway in gynecological malignancies and some focused on the function of COX-2 and cAMP-linked EP2/EP4 and EP3 signaling pathway in gynecological cancer. By contrast, roles of EP1 and the exact pathological mechanisms have not been completely clarified. The studies concerning EP receptors in gynecological cancers highlight the potential advantage of combining COX enzyme inhibitors with EP receptor antagonists as therapeutic agents in gynecological cancers. CONCLUSION EPs represent promising anti-inflammation biomarkers for gynecological cancer and may be novel treatment targets in the near future.
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25
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Smith KER, Hitron EE, Russler GA, Baumgarten DA, Bilen MA. Ramucirumab and Docetaxel in Patients with Metastatic Urothelial Carcinoma Harboring Fibroblast Growth Factor Receptor Alterations: A Case Series and Literature Review. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2020; 3:23-26. [PMID: 35756183 PMCID: PMC9208383 DOI: 10.4103/jipo.jipo_22_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/24/2019] [Accepted: 09/27/2019] [Indexed: 11/24/2022]
Abstract
Metastatic urothelial carcinoma (mUC) has a poor prognosis with a 5-year survival probability of 4.8%. The mainstay of first-line treatment is platinum-based chemotherapy. Second-line therapy involves immune checkpoint inhibitors or a fibroblast growth factor receptor (FGFR) inhibitor, erdafitinib, for patients harboring selected FGFR alterations. Several additional agents are under development for the treatment of mUC. Recent studies demonstrate that ramucirumab and docetaxel have clinical activity in mUC. We report two patients with metastatic upper tract urothelial cancer (mUTUC) with FGFR alterations who were heavily pretreated with FGFR inhibitors that later showed response to ramucirumab and docetaxel. Preclinical studies indicate that FGF and VEGF pathways work synergistically, which could explain the observations in our patients. Our findings may represent another treatment option for patients with mUC and FGFR alterations who have progressed on multiple lines of therapy.
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Affiliation(s)
| | - Emilie Elise Hitron
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Greta A Russler
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | | | - Mehmet Asim Bilen
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
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Inhibition of FGFR2-Signaling Attenuates a Homology-Mediated DNA Repair in GIST and Sensitizes Them to DNA-Topoisomerase II Inhibitors. Int J Mol Sci 2020; 21:ijms21010352. [PMID: 31948066 PMCID: PMC6982350 DOI: 10.3390/ijms21010352] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/28/2019] [Accepted: 01/03/2020] [Indexed: 01/30/2023] Open
Abstract
Deregulation of receptor tyrosine kinase (RTK)-signaling is frequently observed in many human malignancies, making activated RTKs the promising therapeutic targets. In particular, activated RTK-signaling has a strong impact on tumor resistance to various DNA damaging agents, e.g., ionizing radiation and chemotherapeutic drugs. We showed recently that fibroblast growth factor receptor (FGFR)-signaling might be hyperactivated in imatinib (IM)-resistant gastrointestinal stromal tumors (GIST) and inhibition of this pathway sensitized tumor cells to the low doses of chemotherapeutic agents, such as topoisomerase II inhibitors. Here, we report that inhibition of FGFR-signaling in GISTs attenuates the repair of DNA double-strand breaks (DSBs), which was evidenced by the delay in γ-H2AX decline after doxorubicin (Dox)-induced DNA damage. A single-cell gel electrophoresis (Comet assay) data showed an increase of tail moment in Dox-treated GIST cells cultured in presence of BGJ398, a selective FGFR1-4 inhibitor, thereby revealing the attenuated DNA repair. By utilizing GFP-based reporter constructs to assess the efficiency of DSBs repair via homologous recombination (HR) and non-homologous end-joining (NHEJ), we found for the first time that FGFR inhibition in GISTs attenuated the homology-mediated DNA repair. Of note, FGFR inhibition/depletion did not reduce the number of BrdU and phospho-RPA foci in Dox-treated cells, suggesting that inhibition of FGFR-signaling has no impact on the processing of DSBs. In contrast, the number of Dox-induced Rad51 foci were decreased when FGFR2-mediated signaling was interrupted/inhibited by siRNA FGFR2 or BGJ398. Moreover, Rad51 and -H2AX foci were mislocalized in FGFR-inhibited GIST and the amount of Rad51 was substantially decreased in -H2AX-immunoprecipitated complexes, thereby illustrating the defect of Rad51 recombinase loading to the Dox-induced DSBs. Finally, as a result of the impaired homology-mediated DNA repair, the increased numbers of hypodiploid (i.e., apoptotic) cells were observed in FGFR2-inhibited GISTs after Dox treatment. Collectively, our data illustrates for the first time that inhibition of FGF-signaling in IM-resistant GIST interferes with the efficiency of DDR signaling and attenuates the homology-mediated DNA repair, thus providing the molecular mechanism of GIST’s sensitization to DNA damaging agents, e.g., DNA-topoisomerase II inhibitors.
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Viswanathan A, Musa A, Murugesan A, Vale JR, Afonso CAM, Konda Mani S, Yli-Harja O, Candeias NR, Kandhavelu M. Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect (Running Title: Cancer Cells Death Signalling Activation). Cells 2019; 8:cells8121624. [PMID: 31842391 PMCID: PMC6953096 DOI: 10.3390/cells8121624] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/07/2019] [Accepted: 12/09/2019] [Indexed: 12/27/2022] Open
Abstract
Glioblastoma (GB), a grade IV glioma, with high heterogeneity and chemoresistance, obligates a multidimensional antagonist to debilitate its competence. Considering the previous reports on thioesters as antitumor compounds, this paper investigates on use of this densely functionalized sulphur rich molecule as a potent anti-GB agent. Bio-evaluation of 12 novel compounds, containing α-thioether ketone and orthothioester functionalities, identified that five analogs exhibited better cytotoxic profile compared to standard drug cisplatin. Detailed toxicity studies of top compound were evaluated in two cell lines, using cell viability test, apoptotic activity, oxidative stress and caspase activation and RNA-sequencing analysis, to obtain a comprehensive molecular profile of drug activity. The most effective molecule presented half maximal inhibitory concentration (IC50) values of 27 μM and 23 μM against U87 and LN229 GB cells, respectively. Same compound effectively weakened various angiogenic pathways, mainly MAPK and JAK-STAT pathways, downregulating VEGF. Transcriptome analysis identified significant promotion of apoptotic genes, and genes involved in cell cycle arrest, with concurrent inhibition of various tyrosine kinase cascades and stress response genes. Docking and immunoblotting studies suggest EGFR as a strong target of the orthothioester identified. Therefore, orthothioesters can potentially serve as a multi-dimensional chemotherapeutic possessing strong cytotoxic, anti-angiogenic and chemo-sensitization activity, challenging glioblastoma pathogenesis.
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Affiliation(s)
- Anisha Viswanathan
- Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University, BioMeditech and Tays Cancer Center, Tampere University Hospital, P.O. Box 553, 33101 Tampere, Finland; (A.V.); (A.M.)
| | - Aliyu Musa
- Predictive Medicine and Data Analytics Lab, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland;
| | - Akshaya Murugesan
- Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University, BioMeditech and Tays Cancer Center, Tampere University Hospital, P.O. Box 553, 33101 Tampere, Finland; (A.V.); (A.M.)
- Department of Biotechnology, Lady Doak College, Madurai 625002, India
| | - João R. Vale
- Faculty of Engineering and Natural Sciences, Tampere University, 33101 Tampere, Finland;
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;
| | - Carlos A. M. Afonso
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;
| | - Saravanan Konda Mani
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
| | - Olli Yli-Harja
- Computational Systems Biology Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland;
- Institute for Systems Biology, 1441N 34th Street, Seattle, WA 98103-8904, USA
| | - Nuno R. Candeias
- Faculty of Engineering and Natural Sciences, Tampere University, 33101 Tampere, Finland;
- Correspondence: (N.R.C.); (M.K.); Tel.: +358-468857306 (N.R.C.); +358-417488772 (M.K.)
| | - Meenakshisundaram Kandhavelu
- Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University, BioMeditech and Tays Cancer Center, Tampere University Hospital, P.O. Box 553, 33101 Tampere, Finland; (A.V.); (A.M.)
- Correspondence: (N.R.C.); (M.K.); Tel.: +358-468857306 (N.R.C.); +358-417488772 (M.K.)
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Kou X, Sun Y, Li S, Bian W, Liu Z, Zhang D, Jiang J. Pharmacology Study of the Multiple Angiogenesis Inhibitor RC28-E on Anti-Fibrosis in a Chemically Induced Lung Injury Model. Biomolecules 2019; 9:biom9110644. [PMID: 31652997 PMCID: PMC6920960 DOI: 10.3390/biom9110644] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/18/2019] [Accepted: 10/22/2019] [Indexed: 11/30/2022] Open
Abstract
Background: Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminate in tissue fibrosis, inflammation, and angiogenesis simultaneously. Multiple cell angiogenesis is an essential part of the tissue damage response, which is involved in fibrosis development. RC28-E is a novel recombinant dual decoy receptor lgG1 Fc-fusion protein that can block vascular endothelial growth factor (VEGFA), platelet-derived growth factor (PDGF), and fibroblast growth factor-2 (FGF-2) simultaneously. This protein has stepped into clinical trials (NCT03777254) for the treatment of pathological neovascularization-related diseases. Here, we report on the role of RC28-E during anti-fibrosis and its potential multitarget function in regulating fibrosis. Methods: A bleomycin-induced pulmonary fibrosis C57BL/6 mouse model was established. Hematoxylin and eosin staining (HE) and Masson staining (Masson’s) were performed to evaluate the pulmonary fibrosis based on the scoring from, Ashcroft score. Fibrosis related factors and inflammatory cytokines including HYP, α-SMA, procollagen, ICAM, IL-6, IL-1, and TNF-α were also determined at the protein and mRNA levels to characterize the fibrosis. Both mRNA and protein levels of VEGF, FGF, and transforming growth factor (TGF)-β were detected by quantitative real-time PCR (qRT-PCR) and immunohistochemical (IHC) analysis, respectively. Pulmonary fibrosis and related cytokines were re-evaluated in vivo after 3 doses of RC28-E (5 mg/kg, 15 mg/kg, and 50 mg/kg, ip. Tiw × 9) in comparison with a mono-target antagonist treatment (VEGF or FGF blocking). RC28-E attenuated the activation of TGF-β induced fibroblasts in vitro. Expression levels of α-SMA and collagen I, as well as proliferation and migration, were determined with the human skin fibroblast cell line Detroit 551 and primary murine pulmonary fibroblast cells. The mechanism of RC28-E via the TGF-β/Smad pathway was also investigated. Results: RC28-E exhibits significant anti-fibrosis effects on Idiopathic pulmonary fibrosis (IPF) in vivo. Moreover, TGF-β induced fibroblast activation in vitro via the inhibition of the TGF-β downstream Smad pathway, thus providing potential therapeutics for clinical disease-related fibrosis-like IPF as well as chemotherapy-induced fibrosis in cancer therapy.
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Affiliation(s)
- Xiangying Kou
- Department of Pharmacology, Binzhou Medical University, Yantai 256603, China.
| | - Yeying Sun
- Department of Pharmacology, Binzhou Medical University, Yantai 256603, China.
| | - Shenjun Li
- RemeGen Co., Ltd., Yantai 264006, China.
| | - Weihua Bian
- Department of Pharmacology, Binzhou Medical University, Yantai 256603, China.
| | - Zhihao Liu
- RemeGen Co., Ltd., Yantai 264006, China.
| | - Daolai Zhang
- Department of Pharmacology, Binzhou Medical University, Yantai 256603, China.
| | - Jing Jiang
- Department of Pharmacology, Binzhou Medical University, Yantai 256603, China.
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29
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Incio J, Ligibel JA, McManus DT, Suboj P, Jung K, Kawaguchi K, Pinter M, Babykutty S, Chin SM, Vardam TD, Huang Y, Rahbari NN, Roberge S, Wang D, Gomes-Santos IL, Puchner SB, Schlett CL, Hoffmman U, Ancukiewicz M, Tolaney SM, Krop IE, Duda DG, Boucher Y, Fukumura D, Jain RK. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci Transl Med 2019. [PMID: 29540614 DOI: 10.1126/scitranslmed.aag0945] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Anti-vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy's lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.
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Affiliation(s)
- Joao Incio
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.,I3S, Institute for Innovation and Research in Health, Metabolism, Nutrition, and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto 4200-135, Portugal.,Department of Internal Medicine, Hospital S. João, Porto 4200-319, Portugal
| | - Jennifer A Ligibel
- Dana-Farber Cancer Center, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel T McManus
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Priya Suboj
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Botany and Biotechnology, St. Xavier's College, Thumba, Trivandrum, Kerala 695586, India
| | - Keehoon Jung
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Kosuke Kawaguchi
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Matthias Pinter
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
| | - Suboj Babykutty
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala 695015, India
| | - Shan M Chin
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Trupti D Vardam
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Yuhui Huang
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Nuh N Rahbari
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Sylvie Roberge
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Dannie Wang
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Igor L Gomes-Santos
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.,Heart Institute (Instituto do Coração-Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo), University of Sao Paulo Medical School, Sao Paulo 05403-900, Brazil
| | - Stefan B Puchner
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Christopher L Schlett
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Udo Hoffmman
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Marek Ancukiewicz
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Sara M Tolaney
- Dana-Farber Cancer Center, Harvard Medical School, Boston, MA 02115, USA
| | - Ian E Krop
- Dana-Farber Cancer Center, Harvard Medical School, Boston, MA 02115, USA
| | - Dan G Duda
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Yves Boucher
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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30
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Inhibition of fibroblast growth factor receptor-signaling sensitizes imatinib-resistant gastrointestinal stromal tumors to low doses of topoisomerase II inhibitors. Anticancer Drugs 2019; 29:549-559. [PMID: 29697413 DOI: 10.1097/cad.0000000000000637] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The acquired resistance of gastrointestinal stromal tumors (GISTs) to the targeted-based therapy remains the driving force to identify the novel approaches that are capable of increasing the sensitivity of GISTs to the current therapeutic regimens. Our present data show that BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, sensitizes imatinib (IM)-resistant GIST cells with receptor tyrosine kinase (RTK) switch (loss of c-KIT/gain of pFGFR2a) to the low doses of topoisomerase II inhibitors - doxorubicin (Dox) and etoposide (Eto). Mechanistically, pretreatment of IM-resistant GIST cells with BGJ398 for 12 h markedly enhanced proapoptotic and growth-suppressive effects of Dox (or Eto). Indeed, a significant cleavage of PARP and caspase-3 was observed in GIST cells treated with a combination of FGFR and topoisomerase II inhibitor. In contrast, no signs of apoptosis were detected in IM-resistant GIST cells treated with BGJ398, whereas the low doses of Dox (Eto) exerted the minor proapoptotic effects on GISTs. The mechanism of BGJ398-induced sensitization of GIST to topoisomerase II inhibitors might be because of attenuation of DNA damage signaling and repair. Indeed, we observed a marked decrease in Rad51 expression in GIST cells treated with BGJ398 together with Dox. Similar results were obtained when an overexpressed pFGFR2a was knocked down by corresponding siRNA before Dox (Eto) exposure. Moreover, FGFR inhibition/depletion caused a loss of Rad51 foci in Dox-treated GIST cells, suggesting that FGFR-signaling plays an important regulatory role in homology-mediated DNA repair. Our data show that combined therapy (RTKs inhibitors supplemented with low doses of topoisomerase II inhibitors) might be effective for unresectable and metastatic forms of GISTs. In case of resistance to IM because of RTKs switch indicated above, FGFR inhibitors (e.g. BGJ398) might be potentially useful because of their ability to sensitize tumor cells to topoisomerase II inhibitors and induce tumor cell apoptosis by targeting DNA double-strand breaks repair.
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31
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Zhang Q, Lu S, Li T, Yu L, Zhang Y, Zeng H, Qian X, Bi J, Lin Y. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:173. [PMID: 31023337 PMCID: PMC6482513 DOI: 10.1186/s13046-019-1156-5] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 03/27/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear. METHODS The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model. RESULTS ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs. CONCLUSIONS Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway. TRIAL REGISTRATION Retrospectively registered.
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Affiliation(s)
- Qi Zhang
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.,Guangdong Key Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Sihong Lu
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.,Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Tianfu Li
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Liang Yu
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Yunjian Zhang
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Huijuan Zeng
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Xueke Qian
- The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China
| | - Jiong Bi
- Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.
| | - Ying Lin
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.
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32
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Fountzilas E, Palmer G, Vining D, Tsimberidou AM. Prolonged Partial Response to Bevacizumab and Valproic Acid in a Patient With Glioblastoma. JCO Precis Oncol 2018; 2. [PMID: 31544169 DOI: 10.1200/po.18.00282] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
| | | | - David Vining
- The University of Texas MD Anderson Cancer Center, Houston, TX
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33
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Molecular interactions in juvenile nasopharyngeal angiofibroma: preliminary signature and relevant review. Eur Arch Otorhinolaryngol 2018; 276:93-100. [PMID: 30387011 DOI: 10.1007/s00405-018-5178-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 10/17/2018] [Indexed: 12/14/2022]
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34
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Carmen-Orozco RP, Dávila-Villacorta DG, Cauna Y, Bernal-Teran EG, Bitterfeld L, Sutherland GL, Chile N, Céliz RH, Ferrufino-Schmidt MC, Gavídia CM, Sterling CR, García HH, Gilman RH, Verástegui MR. Blood-brain barrier disruption and angiogenesis in a rat model for neurocysticercosis. J Neurosci Res 2018; 97:137-148. [PMID: 30315659 DOI: 10.1002/jnr.24335] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 09/13/2018] [Accepted: 09/14/2018] [Indexed: 12/13/2022]
Abstract
Neurocysticercosis (NCC) is a helminth infection affecting the central nervous system caused by the larval stage (cysticercus) of Taenia solium. Since vascular alteration and blood-brain barrier (BBB) disruption contribute to NCC pathology, it is postulated that angiogenesis could contribute to the pathology of this disease. This study used a rat model for NCC and evaluated the expression of two angiogenic factors called vascular endothelial growth factor (VEGF-A) and fibroblast growth factor (FGF2). Also, two markers for BBB disruption, the endothelial barrier antigen and immunoglobulin G, were evaluated using immunohistochemical and immunofluorescence techniques. Brain vasculature changes, BBB disruption, and overexpression of angiogenesis markers surrounding viable cysts were observed. Both VEGF-A and FGF2 were overexpressed in the tissue surrounding the cysticerci, and VEGF-A was overexpressed in astrocytes. Vessels showed decreased immunoreactivity to endothelial barrier antigen marker and an extensive staining for IgG was found in the tissues surrounding the cysts. Additionally, an endothelial cell tube formation assay using human umbilical vein endothelial cells showed that excretory and secretory antigens of T. solium cysticerci induce the formation of these tubes. This in vitro model supports the hypothesis that angiogenesis in NCC might be caused by the parasite itself, as opposed to the host inflammatory responses alone. In conclusion, brain vasculature changes, BBB disruption, and overexpression of angiogenesis markers surrounding viable cysts were observed. This study also demonstrates that cysticerci excretory-secretory processes alone can stimulate angiogenesis.
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Affiliation(s)
- Rogger P Carmen-Orozco
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Danitza G Dávila-Villacorta
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Yudith Cauna
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Edson G Bernal-Teran
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Leandra Bitterfeld
- The Department of International Health, Bloomberg School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland
| | - Graham L Sutherland
- The Department of International Health, Bloomberg School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland
| | - Nancy Chile
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Rensson H Céliz
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - María C Ferrufino-Schmidt
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Cesar M Gavídia
- School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Perú
| | - Charles R Sterling
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona
| | - Héctor H García
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú.,Cysticercosis Unit, Instituto de Nacional Ciencias Neurológicas, Lima, Perú
| | - Robert H Gilman
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú.,The Department of International Health, Bloomberg School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland.,Asociación Benéfica PRISMA, Lima, Perú
| | - Manuela Renee Verástegui
- Infectious Diseases Laboratory Research-LID, Faculty of Science and Philosophy, Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia, Lima, Perú
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35
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Holmström TH, Moilanen AM, Ikonen T, Björkman ML, Linnanen T, Wohlfahrt G, Karlsson S, Oksala R, Korjamo T, Samajdar S, Rajagopalan S, Chelur S, Narayanan K, Ramachandra RK, Mani J, Nair R, Gowda N, Anthony T, Dhodheri S, Mukherjee S, Ujjinamatada RK, Srinivas N, Ramachandra M, Kallio PJ. ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity. Mol Cancer Ther 2018; 18:28-38. [PMID: 30301864 DOI: 10.1158/1535-7163.mct-18-0204] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 08/20/2018] [Accepted: 10/04/2018] [Indexed: 11/16/2022]
Abstract
Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nmol/L) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent antitumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR and angigogenesis models.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Jiju Mani
- Aurigene Discovery Technologies Limited, India
| | - Rashmi Nair
- Aurigene Discovery Technologies Limited, India
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Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1). Sci Rep 2018; 8:14724. [PMID: 30283071 PMCID: PMC6170482 DOI: 10.1038/s41598-018-33037-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 09/18/2018] [Indexed: 12/29/2022] Open
Abstract
VEGF signaling through its tyrosine kinase receptor, VEGFR2 (FLK1), is critical for tumor angiogenesis. Previous studies have identified a critical gene dosage effect of VegfA in embryonic development and vessel homeostasis, neovascularization, and tumor growth, and potent inhibitors of VEGFR2 have been used to treat a variety of cancers. Inhibition of FGFR signaling has also been considered as an antiangiogenic approach to treat a variety of cancers. Inhibition of VEGFR2 with neutralizing antibodies or with pharmacological inhibitors of the VEGFR tyrosine kinase domain has at least short-term efficacy with some cancers; however, also affects vessel homeostasis, leading to adverse complications. We investigate gene dosage effects of Vegfr2, Fgfr1, and Fgfr2 in three independent mouse models of tumorigenesis: two-stage skin chemical carcinogenesis, and sub-cutaneous transplantation of B16F0 melanoma and Lewis Lung Carcinoma (LLC). Mice heterozygous for Vegfr2 display profound defects in supporting tumor growth and angiogenesis. Unexpectedly, additional deletion of endothelial Fgfr1 and Fgfr2 in Vegfr2 heterozygous mice shows similar tumor growth and angiogenesis as the Vegfr2 heterozygous mice. Notably, hematopoietic deletion of two alleles of Vegfr2 had minimal impact on tumor growth, with little effect on angiogenesis, reinforcing the importance of endothelial Vegfr2 heterozygosity. These studies reveal previously unrecognized Vegfr2 gene dosage effects in tumor angiogenesis and a lack of synergy between VEGFR2 and endothelial FGFR1/2 signaling during tumor growth.
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37
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Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors. Eur J Med Chem 2018; 154:9-28. [PMID: 29775937 DOI: 10.1016/j.ejmech.2018.05.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 04/08/2018] [Accepted: 05/04/2018] [Indexed: 02/08/2023]
Abstract
Starting from the phase II clinical FGFR inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 aberrant cancer cells were observed. In the SNU-16 xenograft model, compound 25a showed tumor growth inhibition rates of 25.0% and 81.0% at doses of 10 mg/kg and 50 mg/kg, respectively, with 5% and 10%body weight loss. In view of the synergistic potential of FGFs and VEGFs in tumor angiogenesis observed in preclinical studies, the FGFR/VEGFR2 dual inhibitor 25a may achieve better clinical benefits.
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38
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Huang SW, Lien JC, Kuo SC, Huang TF. DDA suppresses angiogenesis and tumor growth of colorectal cancer in vivo through decreasing VEGFR2 signaling. Oncotarget 2018; 7:63124-63137. [PMID: 27517319 PMCID: PMC5325351 DOI: 10.18632/oncotarget.11152] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 07/26/2016] [Indexed: 12/12/2022] Open
Abstract
As angiogenesis is required for tumor growth and metastasis, suppressing angiogenesis is a promising strategy in limiting tumor progression. Vascular endothelial growth factor (VEGF)-A, a critical pro-angiogenic factor, has thus become an attractive target for therapeutic interventions in cancer. In this study, we explored the underlying mechanisms of a novel anthraquinone derivative DDA in suppressing angiogenesis. DDA inhibited VEGF-A-induced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs). DDA also reduced VEGF-A-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization in vivo. VEGF-A-induced VEGFR1, VEGFR2, FAK, Akt, ERK1/2 or STAT3 phosphorylation was reduced in the presence of DDA. In addition, NRP-1 siRNA reduced VEGF-A's enhancing effects in VEGFR2, FAK and Akt phosphorylation and cell proliferation in HUVECs. DDA disrupted VEGF-A-induced complex formation between NRP-1 and VEGFR2. Furthermore, systemic administration of DDA was shown to suppress tumor angiogenesis and growth in in vivo mouse xenograft models. Taken together, we demonstrated in this study that DDA exhibits anti-angiogenic properties through suppressing VEGF-A signaling. These observations also suggest that DDA might be a potential drug candidate for developing anti-angiogenic agent in the field of cancer and angiogenesis-related diseases.
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Affiliation(s)
- Shiu-Wen Huang
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jin-Cherng Lien
- Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
| | - Sheng-Chu Kuo
- Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
| | - Tur-Fu Huang
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Mohd Nafi SN, Idris F, Jaafar H. Cellular and Molecular Changes in MNU-Induced Breast Tumours Injected with PF4 or bFGF. Asian Pac J Cancer Prev 2017; 18:3231-3238. [PMID: 29281877 PMCID: PMC5980876 DOI: 10.22034/apjcp.2017.18.12.3231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background: Angiogenic activity has been considered to reflect important molecular events during breast tumour
development. The present study concerned cellular and molecular changes of MNU-induced breast tumours subjected
to promotion and suppression of angiogenesis. Methods: Female Sprague Dawley rats at the age of 21 days received
MNU at the dose 70 mg/kg of body weight by intraperitoneal injection. Three months post-carcinogen initiation,
mammary tumours were palpated and their growth was monitored. When the tumour diameter reached 1.0 ± 0.05 cm,
rats were given bFGF or PF4 intratumourally at a dose of 10 μg/tumour. Entire palpable tumour were subsequently
excised and subjected to histology examination, IHC staining, and RT-PCR. Results: No critical morphological changes
were observed between pro-angiogenic factor, bFGF, and control groups. However, increase of tumour size with more
necrotic and diffuse areas was notable in tumours after anti-angiogenic PF4 intervention. ER and PR mRNA expression
was significantly up- and down-regulated in bFGF and PF4 groups, respectively. The trends were significantly associated
with peri- and intratumoural MVD counts. However, irrespective of whether we promoted or inhibited angiogenesis,
the expression of EGFR and ERBB2 continued to be significantly increased but this was not significantly associated
with the MVD score. No significant differences in E-cadherin and LR gene expression were noted between intervention
and control groups. Conclusion: ER and PR receptor expression shows consistent responses when tumour angiogenesis
is manipulated either positively or negatively. Our study adds to current understanding that not only do we need to
target hormonal receptors, as presently practiced, but we also need to target endothelial receptors to successfully treat
breast cancer.
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Affiliation(s)
- Siti Norasikin Mohd Nafi
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kota Bharu, Kelantan, Malaysia.
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Wang L, Cai B, Zhou S, Zhu H, Qu L, Wang X, Chen Y. RNA-seq reveals transcriptome changes in goats following myostatin gene knockout. PLoS One 2017; 12:e0187966. [PMID: 29228005 PMCID: PMC5724853 DOI: 10.1371/journal.pone.0187966] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Accepted: 10/30/2017] [Indexed: 12/17/2022] Open
Abstract
Myostatin (MSTN) is a powerful negative regulator of skeletal muscle mass in mammalian species that is primarily expressed in skeletal muscles, and mutations of its encoding gene can result in the double-muscling trait. In this study, the CRISPR/Cas9 technique was used to edit MSTN in Shaanbei Cashmere goats and generate knockout animals. RNA sequencing was used to determine and compare the transcriptome profiles of the muscles from three wild-type (WT) goats, three fibroblast growth factor 5 (FGF5) knockout goats (FGF5+/- group) and three goats with disrupted expression of both the FGF5 and MSTN genes (FM+/- group). The sequence reads were obtained using the Illumina HiSeq 2000 system and mapped to the Capra hircus reference genome using TopHat (v2.0.9). In total, 68.93, 62.04 and 66.26 million clean sequencing reads were obtained from the WT, FM+/- and FGF5+/- groups, respectively. There were 201 differentially expressed genes (DEGs) between the WT and FGF5+/- groups, with 86 down- and 115 up-regulated genes in the FGF5+/- group. Between the WT and FM+/- groups, 121 DEGs were identified, including 81 down- and 40 up-regulated genes in the FM+/- group. A total of 198 DEGs were detected between the FGF5+/- group and FM+/- group, with 128 down- and 70 up-regulated genes in the FM+/- group. At the transcriptome level, we found substantial changes in genes involved in fatty acid metabolism and the biosynthesis of unsaturated fatty acids, such as stearoyl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydratase 2, ELOVL fatty acid elongase 6 and fatty acid synthase, suggesting that the expression levels of these genes may be directly regulated by MSTN and that these genes are likely downstream targets of MSTN with potential roles in lipid metabolism in goats. Moreover, five randomly selected DEGs were further validated with qRT-PCR, and the results were consistent with the transcriptome analysis. The present study provides insight into the unique transcriptome profile of the MSTN knockout goat, which is a valuable resource for studying goat genomics.
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Affiliation(s)
- Lamei Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Bei Cai
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Shiwei Zhou
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Haijing Zhu
- Shaanxi Provincial Engineering and Technology Research Center of Cashmere Goats, Yulin, China
- Life Science Research Center, Yulin University, Yulin, China
| | - Lei Qu
- Shaanxi Provincial Engineering and Technology Research Center of Cashmere Goats, Yulin, China
- Life Science Research Center, Yulin University, Yulin, China
| | - Xiaolong Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yulin Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
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41
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42
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Wang Y, Fu C, Wu Z, Chen L, Chen X, Wei Y, Zhang P. A chitin film containing basic fibroblast growth factor with a chitin-binding domain as wound dressings. Carbohydr Polym 2017; 174:723-730. [DOI: 10.1016/j.carbpol.2017.05.087] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/20/2017] [Accepted: 05/26/2017] [Indexed: 12/15/2022]
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Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids. Proc Natl Acad Sci U S A 2017; 114:4370-4375. [PMID: 28396419 DOI: 10.1073/pnas.1616893114] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.
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44
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Winterhoff B, Konecny GE. Targeting fibroblast growth factor pathways in endometrial cancer. Curr Probl Cancer 2017; 41:37-47. [DOI: 10.1016/j.currproblcancer.2016.11.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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45
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Pessina P, Castillo VA, César D, Sartore I, Meikle A. Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs. Open Vet J 2016; 6:247-254. [PMID: 28116249 PMCID: PMC5223283 DOI: 10.4314/ovj.v6i3.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 12/13/2016] [Indexed: 12/17/2022] Open
Abstract
Immunohistochemical markers (IGF-1, IGF-1R, VEGF, FGF-2, RARα and RXR) were evaluated in healthy canine thyroid glands (n=8) and in follicular-compact (n=8) and compact thyroid carcinomas (n=8). IGF-1, IGF-1R and VEGF expression was higher in fibroblasts and endothelial cells of compact carcinoma than in healthy glands (P < 0.05). Compared to follicular-compact carcinoma, compact carcinoma had higher IGF-1R expression in fibroblasts, and higher FGF-2 expression in endothelial cells (P < 0.05). RARα expression was higher in endothelial cells of compact carcinoma than in those of other groups (P < 0.05). The upregulation of these proliferation- and angiogenesis-related factors in endothelial cells and/or fibroblasts and not in follicular cells of compact carcinoma compared to healthy glands supports the relevance of stromal cells in cancer progression.
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Affiliation(s)
- P Pessina
- Laboratorio de Técnicas Nucleares, Facultad de Veterinaria, Universidad de la República, Lasplaces 1550, Montevideo, Uruguay
| | - V A Castillo
- Cat. Clin. Méd. Peq. An. and U. Endocrinología, Escuela Medicina Veterinaria, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires. Av. Chorroarín 280, C. Autónoma de Buenos Aires, Argentina
| | - D César
- Instituto Plan Agropecuario, Br. Artigas 3802, Montevideo, Uruguay
| | - I Sartore
- Laboratorio de Técnicas Nucleares, Facultad de Veterinaria, Universidad de la República, Lasplaces 1550, Montevideo, Uruguay
| | - A Meikle
- Laboratorio de Técnicas Nucleares, Facultad de Veterinaria, Universidad de la República, Lasplaces 1550, Montevideo, Uruguay
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46
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Fukumura D, Incio J, Shankaraiah RC, Jain RK. Obesity and Cancer: An Angiogenic and Inflammatory Link. Microcirculation 2016; 23:191-206. [PMID: 26808917 DOI: 10.1111/micc.12270] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 01/20/2016] [Indexed: 12/15/2022]
Abstract
With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
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Affiliation(s)
- Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joao Incio
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.,Department of Internal Medicine, Hospital S. João, Porto, Portugal
| | - Ram C Shankaraiah
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Wang S, Qi Y, Yu L, Zhang L, Chao F, Huang W, Huang R, Li H, Luo Y, Xiu Y, Tang Y. Endogenous nitric oxide regulates blood vessel growth factors, capillaries in the cortex, and memory retention in Sprague-Dawley rats. Am J Transl Res 2016; 8:5271-5285. [PMID: 28078001 PMCID: PMC5209481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 11/27/2016] [Indexed: 06/06/2023]
Abstract
The effects of nitric oxide (NO) on cerebral capillary angiogenesis and the regulation of pro- and anti-angiogenic factors that affect cerebral capillary angiogenesis, spatial learning, and memory ability are unclear. We assessed the effects of the NO precursor L-arginine (L-ARG) and the NO synthesis inhibitor Nω-nitro-L-arginine methylester (L-NAME) on cortical capillaries and spatial learning and memory abilities. We administered intracerebroventricular injections of L-ARG or L-NAME to rats before they were evaluated in the Morris water maze. We measured the levels of NO synthase activity, pro-angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2), and the expression of the anti-angiogenic factors angiostatin and endostatin. We also quantitatively investigated parameters of the cortical capillaries using immunohistochemistry and stereological methods. The L-ARG treatment significantly improved rats' spatial learning abilities and increased NOS activity in the cortex. L-NAME disrupted spatial learning. Following the L-ARG treatment, the expression of the pro-angiogenic factors (VEGF and FGF-2) was higher and the expression of anti-angiogenic factors (endostatin) was lower than the vehicle-treated animals. In contrast, the L-NAME treatment reduced the expression of VEGF and increased the expression of endostatin. Based on these results, modulation of the NO content in the brain regulates VEGF, FGF-2, and endostatin expression, as well as capillary parameters in the cortex, which in turn influence spatial learning and memory performance.
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Affiliation(s)
- Sanrong Wang
- Department of Rehabilitation Medicine and Physical Therapy, Second Affiliated Hospital, Chongqing Medical UniversityChongqing, P. R. China
| | - Yingqiang Qi
- Department of Histology and Embryology, Chongqing Medical UniversityChongqing, P. R. China
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing, P. R. China
| | - Lehua Yu
- Department of Rehabilitation Medicine and Physical Therapy, Second Affiliated Hospital, Chongqing Medical UniversityChongqing, P. R. China
| | - Lei Zhang
- Department of Histology and Embryology, Chongqing Medical UniversityChongqing, P. R. China
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing, P. R. China
| | - Fenglei Chao
- Department of Histology and Embryology, Chongqing Medical UniversityChongqing, P. R. China
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing, P. R. China
| | - Wei Huang
- Department of Histology and Embryology, Chongqing Medical UniversityChongqing, P. R. China
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing, P. R. China
| | - Rongzhong Huang
- Department of Rehabilitation Medicine and Physical Therapy, Second Affiliated Hospital, Chongqing Medical UniversityChongqing, P. R. China
| | - Hongxu Li
- Department of Rehabilitation Medicine and Physical Therapy, Second Affiliated Hospital, Chongqing Medical UniversityChongqing, P. R. China
| | - Yanming Luo
- Department of Histology and Embryology, Chongqing Medical UniversityChongqing, P. R. China
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing, P. R. China
| | - Yun Xiu
- Department of Histology and Embryology, Chongqing Medical UniversityChongqing, P. R. China
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing, P. R. China
| | - Yong Tang
- Department of Histology and Embryology, Chongqing Medical UniversityChongqing, P. R. China
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing, P. R. China
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Toimela T, Huttala O, Sabell E, Mannerström M, Sarkanen JR, Ylikomi T, Heinonen T. Intra-laboratory validated human cell-based in vitro vasculogenesis/angiogenesis test with serum-free medium. Reprod Toxicol 2016; 70:116-125. [PMID: 27915012 DOI: 10.1016/j.reprotox.2016.11.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/11/2016] [Accepted: 11/28/2016] [Indexed: 01/27/2023]
Abstract
Vasculogenesis and angiogenesis are the processes by which new blood vessels are formed. We have developed a serum-free human adipose stromal cell and umbilical cord vein endothelial cell based vasculogenesis/angiogenesis test. In this study, the test was validated in our GLP laboratory following the OECD Guidance Document 34 [1] using erlotinib, acetylic salicylic acid, levamisole, 2-methoxyestradiol, anti-VEGF, methimazole, and D-mannitol to show its reproducibility, repeatability, and predictivity for humans. The results were obtained from immunostained tubule structures and cytotoxicity assessment. The performance of the test was evaluated using 26 suspected teratogens and non-teratogens. The positive predictive value was 71.4% and the negative predictive value was 50.0%, indicating that inhibition of vasculogenesis is a significant mechanism behind teratogenesis. In conclusion, this test has great potential to be a screening test for prioritization purposes of chemicals and to be a test in a battery to predict developmental hazards in a regulatory context.
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Affiliation(s)
- T Toimela
- FICAM, University of Tampere, Finland.
| | - O Huttala
- FICAM, University of Tampere, Finland
| | - E Sabell
- FICAM, University of Tampere, Finland
| | | | - J R Sarkanen
- Cell Biology, University of Tampere, Finland; Science Center, Tampere University Hospital, Finland
| | - T Ylikomi
- Cell Biology, University of Tampere, Finland; Science Center, Tampere University Hospital, Finland
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Avizienyte E, Cole CL, Rushton G, Miller GJ, Bugatti A, Presta M, Gardiner JM, Jayson GC. Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo. PLoS One 2016; 11:e0159739. [PMID: 27490176 PMCID: PMC4973927 DOI: 10.1371/journal.pone.0159739] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 07/07/2016] [Indexed: 11/23/2022] Open
Abstract
Heparan sulphate (HS), a ubiquitously expressed glycosaminoglycan (GAG), regulates multiple cellular functions by mediating interactions between numerous growth factors and their cell surface cognate receptors. However, the structural specificity of HS in these interactions remains largely undefined. Here, we used completely synthetic, structurally defined, alternating N-sulfated glucosamine (NS) and 2-O-sulfated iduronate (IS) residues to generate dodecasaccharides ([NSIS]6) that contained no, one or six glucosamine 6-O-sulfates (6S). The aim was to address how 6S contributes to the potential of defined HS dodecasaccharides to inhibit the angiogenic growth factors FGF2 and VEGF165, in vitro and in vivo. We show that the addition of a single 6S at the non-reducing end of [NSIS]6, i.e. [NSIS6S]-[NSIS]5, significantly augments the inhibition of FGF2-dependent endothelial cell proliferation, migration and sprouting in vitro when compared to the non-6S variant. In contrast, the fully 6-O-sulfated dodecasaccharide, [NSIS6S]6, is not a potent inhibitor of FGF2. Addition of a single 6S did not significantly improve inhibitory properties of [NSIS]6 when tested against VEGF165-dependent endothelial cell functions.In vivo, [NSIS6S]-[NSIS]5 blocked FGF2-dependent blood vessel formation without affecting tumor growth. Reduction of non-FGF2-dependent ovarian tumor growth occurred when [NSIS6S]-[NSIS]5 was combined with cisplatin. The degree of inhibition by [NSIS6S]-[NSIS]5 in combination with cisplatin in vivo equated with that induced by bevacizumab and sunitinib when administered with cisplatin. Evaluation of post-treatment vasculature revealed that [NSIS6S]-[NSIS]5 treatment had the greatest impact on tumor blood vessel size and lumen formation. Our data for the first time demonstrate that synthetic, structurally defined oligosaccharides have potential to be developed as active anti-angiogenic agents that sensitize tumors to chemotherapeutic agents.
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Affiliation(s)
- Egle Avizienyte
- Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom
- * E-mail: (EA); (GCJ)
| | - Claire L. Cole
- Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom
| | - Graham Rushton
- Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom
| | - Gavin J. Miller
- School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7ND, United Kingdom
| | - Antonella Bugatti
- Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Marco Presta
- Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - John M. Gardiner
- School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7ND, United Kingdom
| | - Gordon C. Jayson
- Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom
- * E-mail: (EA); (GCJ)
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50
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Babarović E, Valković T, Budisavljević I, Balen I, Štifter S, Duletić-Načinović A, Lučin K, Jonjić N. The expression of osteopontin and vascular endothelial growth factor in correlation with angiogenesis in monoclonal gammopathy of undetermined significance and multiple myeloma. Pathol Res Pract 2016; 212:509-16. [DOI: 10.1016/j.prp.2015.11.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 10/24/2015] [Accepted: 11/23/2015] [Indexed: 01/24/2023]
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