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European Journal of Pharmacology Jun 2023Angiogenesis is a double-edged sword; it is a mechanism that defines the boundary between health and disease. In spite of its central role in physiological homeostasis,... (Review)
Review
Angiogenesis is a double-edged sword; it is a mechanism that defines the boundary between health and disease. In spite of its central role in physiological homeostasis, it provides the oxygen and nutrition needed by tumor cells to proceed from dormancy if pro-angiogenic factors tip the balance in favor of tumor angiogenesis. Among pro-angiogenic factors, vascular endothelial growth factor (VEGF) is a prominent target in therapeutic methods due to its strategic involvement in the formation of anomalous tumor vasculature. In addition, VEGF exhibits immune-regulatory properties which suppress immune cell antitumor activity. VEGF signaling through its receptors is an integral part of tumoral angiogenic approaches. A wide variety of medicines have been designed to target the ligands and receptors of this pro-angiogenic superfamily. Herein, we summarize the direct and indirect molecular mechanisms of VEGF to demonstrate its versatile role in the context of cancer angiogenesis and current transformative VEGF-targeted strategies interfering with tumor growth.
Topics: Humans; Angiogenesis Inhibitors; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 36906141
DOI: 10.1016/j.ejphar.2023.175586 -
Hypertension (Dallas, Tex. : 1979) Mar 2023Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease,... (Review)
Review
Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease, and hypertension. One of the most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors. Adjunctive therapy, including corticosteroids, calcineurin inhibitors, and nonsteroidal anti-inflammatories, as well as anti-androgen hormone therapy for prostate cancer, may further increase blood pressure in these patients. Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment. The exact molecular mechanisms underlying hypertension are unclear, but recent discoveries indicate an important role for reduced nitric oxide generation, oxidative stress, endothelin-1, prostaglandins, endothelial dysfunction, increased sympathetic outflow, and microvascular rarefaction. In addition, genetic polymorphisms in vascular endothelial growth factor receptors are implicated in vascular endothelial growth factor inhibitor-induced hypertension. Diagnosis, management, and follow-up of cancer therapy-induced hypertension follow national hypertension guidelines because evidence-based clinical trials specifically addressing patients who develop hypertension as a result of cancer therapy are currently lacking. Rigorous baseline assessment of patients before therapy is started requires particular emphasis on assessing and treating cardiovascular risk factors. Hypertension management follows guidelines for the general population, although special attention should be given to rebound hypotension after termination of cancer therapy. Management of these complex patients requires collaborative care involving oncologists, cardiologists, hypertension specialists, primary care professionals, and pharmacists to ensure the optimal therapeutic effect from cancer treatment while minimizing competing cardiovascular toxicities.
Topics: Male; Humans; Vascular Endothelial Growth Factor A; American Heart Association; Hypertension; Antineoplastic Agents; Angiogenesis Inhibitors; Neoplasms
PubMed: 36621810
DOI: 10.1161/HYP.0000000000000224 -
Frontiers in Immunology 2020Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard... (Review)
Review
Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.
Topics: Angiogenesis Inhibitors; Animals; B7-H1 Antigen; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Clinical Trials as Topic; Humans; Immune Checkpoint Inhibitors; Immunomodulation; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Prognosis; Signal Transduction; Treatment Outcome; Tumor Microenvironment
PubMed: 33250900
DOI: 10.3389/fimmu.2020.598877 -
Expert Opinion on Therapeutic Patents Dec 2023Angiogenesis plays a crucial role in the development of numerous vascular structures and is involved in a variety of physiologic and pathologic processes, including... (Review)
Review
INTRODUCTION
Angiogenesis plays a crucial role in the development of numerous vascular structures and is involved in a variety of physiologic and pathologic processes, including psoriasis, diabetic retinopathy, and especially cancer. By obstructing the process of angiogenesis, these therapies effectively inhibit the progression of the disease. Consequently, anti-angiogenic agents were subsequently developed.
AREAS COVERED
This review provides a comprehensive summary of the anti-angiogenic inhibitors developed in the past five years in terms of chemical structure, biochemical/pharmacological activity and potential clinical applications. A literature search was conducted using utilizing the databases Web of Science, SciFinder and PubMed with the key word 'anti-angiogenic agents' and 'angiogenesis inhibitor.'
EXPERT OPINION
This is despite the fact that the concept of antiangiogenesis has been proposed for more than 50 years and angiogenesis inhibitors are extensively employed in clinical practice. However, significant challenges continue to confront them. In recent years, there has been a significant increase in the number of patents focusing on angiogenesis inhibitors. These patents aim to enhance the selectivity of drugs against VEGF/VEGFR, explore new targets to overcome drug resistance, and explore potential drug combinations, thereby expanding the therapeutic possibilities in this field.
Topics: Humans; Angiogenesis Inhibitors; Neovascularization, Pathologic; Patents as Topic; Neoplasms
PubMed: 38084667
DOI: 10.1080/13543776.2023.2294808 -
Biomolecules May 2021Angiogenesis, a fundamental process in human physiology and pathology, has attracted considerable attention owing to its potential as a therapeutic strategy. Vascular... (Review)
Review
Angiogenesis, a fundamental process in human physiology and pathology, has attracted considerable attention owing to its potential as a therapeutic strategy. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are deemed major mediators of angiogenesis. To date, inhibition of the VEGF-A/VEGFR-2 axis has been an effective strategy employed in the development of anticancer drugs. However, some limitations, such as low efficacy and side effects, need to be addressed. Several drug candidates have been discovered, including small molecule compounds, recombinant proteins, and oligosaccharides. In this review, we focus on human oligosaccharides as modulators of angiogenesis. In particular, sialylated human milk oligosaccharides (HMOs) play a significant role in the inhibition of VEGFR-2-mediated angiogenesis. We discuss the structural features concerning the interaction between sialylated HMOs and VEGFR-2 as a molecular mechanism of anti-angiogenesis modulation and its effectiveness in vivo experiments. In the current state, extensive clinical trials are required to develop a novel VEGFR-2 inhibitor from sialylated HMOs.
Topics: Angiogenesis Inhibitors; Humans; Milk, Human; Neovascularization, Pathologic; Oligosaccharides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 34064180
DOI: 10.3390/biom11060775 -
Cancer Science Mar 2024The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence... (Review)
Review
The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.
Topics: Humans; Colorectal Neoplasms; Vascular Endothelial Growth Factor A; Signal Transduction; Angiogenesis Inhibitors; China; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 38233340
DOI: 10.1111/cas.16063 -
Molecules (Basel, Switzerland) Oct 2020Ginsenoside Rg3 (Rg3) is a member of the ginsenoside family of chemicals extracted from . Like other ginsenosides, Rg3 has two epimers: 20(S)-ginsenoside Rg3 (SRg3) and... (Review)
Review
Ginsenoside Rg3 (Rg3) is a member of the ginsenoside family of chemicals extracted from . Like other ginsenosides, Rg3 has two epimers: 20(S)-ginsenoside Rg3 (SRg3) and 20(R)-ginsenoside Rg3 (RRg3). Rg3 is an intriguing molecule due to its anti-cancer properties. One facet of the anti-cancer properties of Rg3 is the anti-angiogenic action. This review describes the controversies on the effects and effective dose range of Rg3, summarizes the evidence on the efficacy of Rg3 on angiogenesis, and raises the possibility that Rg3 is a prodrug.
Topics: Angiogenesis Inhibitors; Animals; Ginsenosides; Humans; Neovascularization, Physiologic; Prodrugs
PubMed: 33113992
DOI: 10.3390/molecules25214905 -
Advances in Experimental Medicine and... 2020Thrombospondins (TSPs) are multifaceted proteins that contribute to physiologic as well as pathologic conditions. Due to their multiple receptor-binding domains, TSPs... (Review)
Review
Thrombospondins (TSPs) are multifaceted proteins that contribute to physiologic as well as pathologic conditions. Due to their multiple receptor-binding domains, TSPs display both oncogenic and tumor-suppressive qualities and are thus essential components of the extracellular matrix. Known for their antiangiogenic capacity, TSPs are an important component of the tumor microenvironment. The N- and C-terminal domains of TSP are, respectively, involved in cell adhesion and spreading, an important feature of wound healing as well as cancer cell migration. Previously known for the activation of TGF-β to promote tumor growth and inflammation, TSP-1 has recently been found to be transcriptionally induced by TGF-β, implying the presence of a possible feedback loop. TSP-1 is an endogenous inhibitor of T cells and also mediates its immunosuppressive effects via induction of Tregs. Given the diverse roles of TSPs in the tumor microenvironment, many therapeutic strategies have utilized TSP-mimetic peptides or antibody blockade as anti-metastatic approaches. This chapter discusses the diverse structural domains, functional implications, and anti-metastatic therapies in the context of the role of TSP in the tumor microenvironment.
Topics: Angiogenesis Inhibitors; Cell Movement; Humans; Neoplasms; Thrombospondins; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 32845506
DOI: 10.1007/978-3-030-48457-6_8 -
Drug Discovery Today Feb 2023Angiogenesis and metastasis are two interdependent cancer hallmarks, the latter of which is the key cause of treatment failure. Thus, establishing effective... (Review)
Review
Angiogenesis and metastasis are two interdependent cancer hallmarks, the latter of which is the key cause of treatment failure. Thus, establishing effective antiangiogenesis/antimetastasis agents is the final frontier in cancer research. Gold nanoparticles (GNPs) may provide disruptive advancements in this regard due to their intrinsic physical and physiological features. Here, we comprehensively discuss recent potential therapeutical strategies to treat angiogenesis and metastasis and present a critical review on the state-of-the-art in vitro and in vivo evaluations of the antiangiogenic/antimetastatic activity of GNPs. Finally, we provide perspectives on the contribution of GNPs to the advancement of cancer management.
Topics: Humans; Gold; Metal Nanoparticles; Antineoplastic Agents; Neoplasms; Angiogenesis Inhibitors
PubMed: 36375738
DOI: 10.1016/j.drudis.2022.103438 -
Drugs Dec 2019Brolucizumab (Beovu) is a low molecular weight, single-chain antibody fragment vascular endothelial growth factor (VEGF) inhibitor being developed by Novartis for the... (Review)
Review
Brolucizumab (Beovu) is a low molecular weight, single-chain antibody fragment vascular endothelial growth factor (VEGF) inhibitor being developed by Novartis for the treatment of exudative (wet) age-related macular degeneration (AMD), diabetic macular oedema and macular oedema secondary to retinal vein occlusion. Based primarily on the results of the phase III HAWK and HARRIER trials brolucizumab was recently approved in the US for the treatment of wet AMD. This article summarizes the milestones in the development of brolucizumab leading to this first approval.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Clinical Trials, Phase III as Topic; Drug Approval; Humans; Macular Degeneration; Vascular Endothelial Growth Factor A
PubMed: 31768932
DOI: 10.1007/s40265-019-01231-9