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Asia-Pacific Journal of Clinical... Aug 2019Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various... (Review)
Review
Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various anti-angiogenic therapies, such as antivascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR)-2 monoclonal antibodies, VEGF-Trap and VEGFR tyrosine kinase inhibitors, the anti-VEGFR-2 antibody ramucirumab was shown to prolong overall survival not only as a single agent but also in combination with paclitaxel as a second-line chemotherapy. Additionally, apatinib, a selective VEGFR-2 tyrosine kinase inhibitor, prolonged survival as a third-line or later treatment option in patients with advanced gastric cancer. Preliminary results of studies investigating ramucirumab plus immune checkpoint inhibitors in gastric cancer were encouraging, and further investigations are ongoing. In China, apatinib in combination with cytotoxic agents is being investigated for systemic chemotherapy or maintenance therapy as an earlier treatment option. The clinical activity in gastric cancer of the multikinase inhibitor regorafenib was suggested in a randomized phase II study. A global phase III trial comparing regorafenib with placebo is currently ongoing. Further studies of anti-angiogenic therapy combined with not only chemotherapy but also immune checkpoint inhibitors are also being pursued, providing hope for improved survival in patients with gastric cancer.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Humans; Stomach Neoplasms
PubMed: 31111678
DOI: 10.1111/ajco.13174 -
European Journal of Medicinal Chemistry Sep 2023Angiogenesis is the biological process in which existing blood vessels generate new ones and it is essential for body growth and development, wound healing, and... (Review)
Review
Angiogenesis is the biological process in which existing blood vessels generate new ones and it is essential for body growth and development, wound healing, and granulation tissue formation. Vascular endothelial growth factor receptor (VEGFR) is a crucial cell membrane receptor that binds to VEGF to regulate angiogenesis and maintenance. Dysregulation of VEGFR signaling can lead to several diseases, such as cancer and ocular neovascular disease, making it a crucial research area for disease treatment. Currently, anti-VEGF drugs commonly used in ophthalmology are mainly four macromolecular drugs, Bevacizumab, Ranibizumab, Conbercept and Aflibercept. Although these drugs are relatively effective in treating ocular neovascular diseases, their macromolecular properties, strong hydrophilicity, and poor blood-eye barrier penetration limit their efficacy. However, VEGFR small molecule inhibitors possess high cell permeability and selectivity, allowing them to traverse and bind to VEGF-A specifically. Consequently, they have a shorter duration of action on the target, and they offer significant therapeutic benefits to patients in the short term. Consequently, there is a need to develop small molecule inhibitors of VEGFR to target ocular neovascularization diseases. This review summarizes the recent developments in potential VEGFR small molecule inhibitors for the targeted treatment of ocular neovascularization diseases, with the aim of providing insights for future studies on VEGFR small molecule inhibitors.
Topics: Humans; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Neovascularization, Pathologic; Neoplasms
PubMed: 37285684
DOI: 10.1016/j.ejmech.2023.115535 -
Current Treatment Options in Oncology Jun 2022Medulloblastoma (MB) is the most frequent pediatric brain tumor. Despite conventional therapy, MB patients have high mortality and morbidity rates mainly due to the... (Review)
Review
Medulloblastoma (MB) is the most frequent pediatric brain tumor. Despite conventional therapy, MB patients have high mortality and morbidity rates mainly due to the incomplete understanding of the molecular and cellular processes involved in development of this cancer. Similar to other solid tumors, MB demonstrated high endothelial cell proliferation and angiogenic activity, wherein new blood vessels arise from the pre-existing vasculature, a process named angiogenesis. MB angiogenesis is considered a hallmark for MB development, progression, and metastasis emphasizing its potential target for antitumor therapy. However, angiogenesis is tightly regulated by a set of angiogenic factors making it a complex process to be targeted. Although agents targeting these factors and their receptors are early in development, the potential for their targeting may translate into improvement in the clinical care for MB patients. In this review, we focus on the most potent angiogenic factors and their corresponding receptors, highlighting their basic properties and expression in MB. We describe their contribution to MB tumorigenesis and angiogenesis and the potential therapeutic targeting of these factors.
Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Cerebellar Neoplasms; Child; Humans; Medulloblastoma; Neovascularization, Pathologic
PubMed: 35412196
DOI: 10.1007/s11864-022-00981-1 -
Biochemical and Biophysical Research... Nov 2021Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment...
Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment development. Given potent anti-cancer efficacy of mefloquine, FDA-approved anti-malarial drug, there is increasing interest in repurposing mefloquine for treatment of cancers, including glioblastoma. In line with these efforts, our work is the first to demonstrate that mefloquine is also an inhibitor of glioblastoma angiogenesis. Using glioblastoma microvascular endothelial cell (GMEC) isolated from glioblastoma patients, we show that mefloquine at clinically achievable concentration inhibits GMEC differentiation, capillary network formation, adhesion to Matrix, growth and survival. Mefloquine also inhibits growth and induces apoptosis in glioblastoma cells regardless of cellular origin and genetic background. We further show that mefloquine significantly inhibits glioblastoma growth but not formation, and this is associated with decreased glioblastoma angiogenesis in mice. Mechanistically, mefloquine disrupted lysosomal integrity and function in GMECs, leading to oxidative stress and lysosomal lipid damage. Rescue studies confirm that mefloquine acts on GMECs in a lysosomal disruption-dependent manner. Our findings demonstrate the anti-angiogenic activity of mefloquine via disrupting lysosomal function. The dual inhibitory role of mefloquine in glioblastoma angiogenesis and glioblastoma displays its advantage over other anti-cancer drugs for glioblastoma treatment. Our work also highlights the essential role of lysosome in both glioblastoma and its angiogenesis.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Male; Mefloquine; Mice, SCID; Neovascularization, Pathologic; Mice
PubMed: 34607260
DOI: 10.1016/j.bbrc.2021.09.069 -
International Journal of Molecular... Jun 2022Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and... (Review)
Review
Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and metastasis. Therefore, there is great interest in developing antiangiogenic strategies. Hypoxia is the basic initiating factor of tumor angiogenesis, which leads to the increase of vascular endothelial growth factor (VEGF), angiopoietin (Ang), hypoxia-inducible factor (HIF-1), etc. in hypoxic cells. The pathways of VEGF and Ang are considered to be critical steps in tumor angiogenesis. A number of antiangiogenic drugs targeting VEGF/VEGFR (VEGF receptor) or ANG/Tie2, or both, are currently being used for cancer treatment, or are still in various stages of clinical development or preclinical evaluation. This article aims to review the mechanisms of angiogenesis and tumor angiogenesis and to focus on new drugs and strategies for the treatment of antiangiogenesis. However, antitumor angiogenic drugs alone may not be sufficient to eradicate tumors. The molecular chaperone heat shock protein 90 (HSP90) is considered a promising molecular target. The VEGFR system and its downstream signaling molecules depend on the function of HSP90. This article also briefly introduces the role of HSP90 in angiogenesis and some HSP90 inhibitors.
Topics: Angiogenesis Inhibitors; Angiopoietins; Antineoplastic Agents; HSP90 Heat-Shock Proteins; Humans; Hypoxia; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 35805939
DOI: 10.3390/ijms23136934 -
Angiogenesis Feb 2020Vessel co-option is a non-angiogenic mechanism of tumour vascularisation in which cancer cells utilise pre-existing blood vessels instead of inducing new blood vessel... (Review)
Review
Vessel co-option is a non-angiogenic mechanism of tumour vascularisation in which cancer cells utilise pre-existing blood vessels instead of inducing new blood vessel formation. Vessel co-option has been observed across a range of different tumour types, in both primary cancers and metastatic disease. Importantly, vessel co-option is now implicated as a major mechanism that mediates resistance to conventional anti-angiogenic drugs and this may help to explain the limited efficacy of this therapeutic approach in certain clinical settings. This includes the use of anti-angiogenic drugs to treat advanced-stage/metastatic disease, treatment in the adjuvant setting and the treatment of primary disease. In this article, we review the available evidence linking vessel co-option with resistance to anti-angiogenic therapy in numerous tumour types, including breast, colorectal, lung and pancreatic cancer, glioblastoma, melanoma, hepatocellular carcinoma, and renal cell carcinoma. The finding that vessel co-option is a significant mechanism of resistance to anti-angiogenic therapy may have important implications for the future of anti-cancer therapy, including (a) predicting response to anti-angiogenic drugs, (b) the need to develop therapies that target both angiogenesis and vessel co-option in tumours, and (c) predicting the response to other therapeutic modalities, including immunotherapy.
Topics: Angiogenesis Inhibitors; Drug Resistance, Neoplasm; Humans; Immunotherapy; Neoplasms; Neovascularization, Pathologic
PubMed: 31865479
DOI: 10.1007/s10456-019-09698-6 -
Chemical Record (New York, N.Y.) Dec 2022Antiangiogenic therapy in combination with chemotherapeutic agents is an effective strategy for cancer treatment. However, this combination therapy is associated with... (Review)
Review
Antiangiogenic therapy in combination with chemotherapeutic agents is an effective strategy for cancer treatment. However, this combination therapy is associated with several challenges including non-specific biodistribution leading to systemic toxicity. Biomaterial-mediated codelivery of chemotherapeutic and anti-angiogenic agents can exploit their passive and active targeting abilities, leading to improved drug accumulation at the tumor site and therapeutic outcomes. In this review, we present the progress made in the field of engineered biomaterials for codelivery of chemotherapeutic and antiangiogenic agents. We present advances in engineering of liposome/hydrogel/micelle-based biomaterials for delivery of combination of anticancer and anti-angiogenesis drugs, or combination of anticancer and siRNA targeting angiogenesis, and targeted nanoparticles. We then present our perspective on developing strategies for targeting angiogenesis and cell proliferation for cancer therapy.
Topics: Humans; Biocompatible Materials; Antineoplastic Agents; Tissue Distribution; Nanoparticles; Neoplasms; Angiogenesis Inhibitors; Cell Proliferation; Drug Delivery Systems
PubMed: 36103616
DOI: 10.1002/tcr.202200152 -
Journal of Thrombosis and Haemostasis :... Aug 2021Over the past two decades, therapies targeting angiogenesis have developed into a major class of cancer therapeutics. The vascular endothelial growth factor (VEGF)... (Review)
Review
Over the past two decades, therapies targeting angiogenesis have developed into a major class of cancer therapeutics. The vascular endothelial growth factor (VEGF) family of signaling proteins, a group of potent angiogenic growth factors, and their receptors represent the main targets of this therapeutic class. To date, 16 antiangiogenic agents have been approved in the United States for the treatment of cancer and several more are in development. An important consideration with antiangiogenic therapy is toxicity, in particular thrombotic and bleeding risks. These complications have emerged as a major clinical concern that may affect the use of these agents in patients both with and without cancer who may already have an elevated risk of thrombosis and bleeding. Although these agents are frequently considered together as a class when contemplating their bleeding and thrombotic risks, in fact the risks for venous thromboembolism, arterial thrombosis, and bleeding vary significantly between different classes of antiangiogenic agents and even among different agents within a class. In this narrative review, we describe the literature investigating the venous and arterial thrombotic and bleeding risks associated with the currently available antiangiogenic drugs. In addition, we discuss these specific complications in the context of both cancer therapy as well as the management of nonmalignant disorders now managed with antiangiogenic agents, including hereditary hemorrhagic telangiectasia and neovascular age-related macular degeneration.
Topics: Angiogenesis Inhibitors; Hemorrhage; Humans; Neoplasms; Neovascularization, Pathologic; Thrombosis; Vascular Endothelial Growth Factor A
PubMed: 33928747
DOI: 10.1111/jth.15354 -
Methods in Molecular Biology (Clifton,... 2021Most of angiogenesis assays were designed and developed during Folkman's era. But the growth of new blood vessels in several pathologic conditions as tumor development... (Review)
Review
Most of angiogenesis assays were designed and developed during Folkman's era. But the growth of new blood vessels in several pathologic conditions as tumor development or inflammation were observed long time ago.The development of new blood vessels was early observed by ancient Egyptians who tried to destroy them by applying empirical methods. From the first observations regarding angiogenesis to a personalized therapy targeting newly formed blood vessels a lot of experimental in vitro and in vivo angiogenesis assays have been developed. The present work will overview the oldest and less known part of angiogenesis assays development, and in addition, it will present the newest data in the experimental field of angiogenesis which is rapidly improved by the needs of new antiangiogenic and antivascular therapy development.
Topics: Angiogenesis Inhibitors; Animals; Biological Assay; Blood Vessels; Humans; Neovascularization, Pathologic
PubMed: 32754806
DOI: 10.1007/978-1-0716-0916-3_1 -
BMC Cancer Aug 2022Lycorine (Lyc) is a natural alkaloid derived from medicinal plants of the Amaryllidaceae family. Lyc has been reported to inhibit the recurrence and metastasis of...
Lycorine (Lyc) is a natural alkaloid derived from medicinal plants of the Amaryllidaceae family. Lyc has been reported to inhibit the recurrence and metastasis of different kinds of tumors. However, Lyc's effect on angiogenesis and its specific mechanism are still not clear. This study was designed to test the antiangiogenesis effect of Lyc and to explore the possible mechanisms. We performed cell experiments to confirm Lyc's inhibitory effect on angiogenesis and employed sunitinib as a positive control. Moreover, the synergistic effect of Lyc and sunitinib was also explored. Next, we conducted bioinformatics analyses to predict the potential targets of Lyc and verified them by western blotting and immunofluorescence. Molecular docking, kinase activity assays, Biacore assays and cellular thermal shift assays (CETSAs) were applied to elucidate the mechanism by which Lyc inhibited target activity. Lyc inhibited angiogenesis in human umbilical vein endothelial cells (HUVECs). Employing bioinformatics, we found that Lyc's target was PDGFRα and that Lyc attenuated PDGFRα phosphorylation. We also found that Lyc inhibited PDGFRα activation by docking to it to restrain its activity. Additionally, Lyc significantly inhibited PDGF-AA-induced angiogenesis. This study provides new insights into the molecular functions of Lyc and indicates its potential as a therapeutic agent for tumor angiogenesis.
Topics: Amaryllidaceae Alkaloids; Angiogenesis Inhibitors; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Humans; Molecular Docking Simulation; Neoplasms; Neovascularization, Pathologic; Phenanthridines; Receptor, Platelet-Derived Growth Factor alpha; Sunitinib
PubMed: 35948939
DOI: 10.1186/s12885-022-09929-y