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Journal of Ocular Pharmacology and... Sep 2015Ocular angiogenesis is one of the underlying causes of blindness and vision impairment and may occur in a spectrum of disorders, including diabetic retinopathy,...
Ocular angiogenesis is one of the underlying causes of blindness and vision impairment and may occur in a spectrum of disorders, including diabetic retinopathy, neovascular age-related macular degeneration, retinal artery or vein occlusion, and retinopathy of prematurity. As such, strategies to inhibit angiogenesis by suppressing vascular endothelial growth factor activity have proven to be effective in the clinic for the treatment of eye diseases. A complementary approach would be to increase the level of naturally occurring inhibitors of angiogenesis, such as thrombospondin (TSP)-1. This article summarizes the development of TSP-1-based inhibitors of angiogenesis.
Topics: Angiogenesis Inhibitors; Blindness; Eye; Eye Diseases; Humans; Neovascularization, Pathologic; Thrombospondin 1
PubMed: 26352160
DOI: 10.1089/jop.2015.0018 -
Annals of Oncology : Official Journal... Sep 2014The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years.... (Review)
Review
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab. Finally, all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Angiogenesis Inhibitors; Antineoplastic Agents; Cancer Vaccines; Drug Discovery; Endothelin Receptor Antagonists; Humans; Immunotherapy; Male; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors
PubMed: 24658665
DOI: 10.1093/annonc/mdu038 -
International Journal of Molecular... Oct 2021Age-related macular degeneration (AMD) is central vision loss with aging, was the fourth main cause of blindness in 2015, and has many risk factors, such as cataract... (Review)
Review
Age-related macular degeneration (AMD) is central vision loss with aging, was the fourth main cause of blindness in 2015, and has many risk factors, such as cataract surgery, cigarette smoking, family history, hypertension, obesity, long-term smart device usage, etc. AMD is classified into three categories: normal AMD, early AMD, and late AMD, based on angiogenesis in the retina, and can be determined by bis-retinoid -retinyl--retinylidene ethanolamine (A2E)-epoxides from the reaction of A2E and blue light. During the reaction of A2E and blue light, reactive oxygen species (ROS) are synthesized, which gather inflammatory factors, induce carbonyl stress, and finally stimulate the death of retinal pigment epitheliums (RPEs). There are several medications for AMD, such as device-based therapy, anti-inflammatory drugs, anti-VEGFs, and natural products. For device-based therapy, two methods are used: prophylactic laser therapy (photocoagulation laser therapy) and photodynamic therapy. Anti-inflammatory drugs consist of corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). Anti-VEGFs are classified antibodies for VEGF, aptamer, soluble receptor, VEGF receptor-1 and -2 antibody, and VEGF receptor tyrosine kinase inhibitor. Finally, additional AMD drug candidates are derived from natural products. For each medication, there are several and severe adverse effects, but natural products have a potency as AMD drugs, as they have been used as culinary materials and/or traditional medicines for a long time. Their major application route is oral administration, and they can be combined with device-based therapy, anti-inflammatory drugs, and anti-VEGFs. In general, AMD drug candidates from natural products are more effective at treating early and intermediate AMD. However, further study is needed to evaluate their efficacy and to investigate their therapeutic mechanisms.
Topics: Angiogenesis Inhibitors; Anti-Inflammatory Agents; Humans; Laser Therapy; Macular Degeneration; Photochemotherapy
PubMed: 34769270
DOI: 10.3390/ijms222111837 -
International Journal of Molecular... Apr 2022A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis...
A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis inhibitors were able to inhibit differentiation and network formation of HUVECs in vitro. The effect of the inhibitors was determined by the morphology and the calculated percentage area covered by HUVECs. Neutralizing VEGF with avastin and polyclonal goat anti-VEGF antibody and inhibiting VEGFR2 with sorafenib and vatalanib resulted in the formation of HUVEC clusters of variable sizes as a result of inhibited EC differentiation. Furthermore, numerous inhibitors of the VEGF signaling pathways were tested for their effect on the growth and differentiation of HUVECs. The effects of these inhibitors did not reveal a cluster morphology, either individually or when combined to block VEGFR2 downstream pathways. Only the addition of -methyl--bromolevamisole revealed a similar morphology as when targeting VEGF and VEGFR2, meaning it may have an inhibitory influence directly on VEGFR signaling. Additionally, several nuclear receptor ligands and miscellaneous compounds that might affect EC growth and differentiation were tested, but only dexamethasone gave rise to cluster formation similarly to VEGF-neutralizing compounds. These results point to a link between angiogenesis, HUVEC differentiation and glucocorticoid receptor activation.
Topics: Angiogenesis Inhibitors; Cell Movement; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 35457095
DOI: 10.3390/ijms23084277 -
Acta Myologica : Myopathies and... Dec 2020Drug-induced myopathies are a group of disorders whose importance lies in the fact that they are potentially treatable and usually reversible if the causative agent is... (Review)
Review
Drug-induced myopathies are a group of disorders whose importance lies in the fact that they are potentially treatable and usually reversible if the causative agent is identified and withdrawn. A wide variety of medications used in many different branches of medicine have been recognised as causing muscle adverse effects, ranging from myalgia and asymptomatic hyperCKaemia to severe weakness and at times fatal rhabdomyolysis. There has been increased awareness of these complications since the introduction of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor group of drugs (statins) in the 1980s, and their subsequent association with a range of necrotising and immune-mediated inflammatory myopathies and muscle symptoms. More recently, since the introduction of the immune checkpoint inhibitors for the treatment of advanced malignancies, it has been increasingly recognised that these drugs also have a propensity to induce or exacerbate a variety of immune-mediated myopathies, neuropathies, myasthenic disorders and atypical overlap syndromes, and it is anticipated that these complications will become even more prevalent with increasing use of these medications in the future. This review focusses mainly on these two groups of drugs, and on cytokine-based therapies and VEGF inhibitors which have also been implicated in the induction of immune-mediated inflammatory myopathies.
Topics: Angiogenesis Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune Checkpoint Inhibitors; Immunosuppressive Agents; Myotoxicity
PubMed: 33458583
DOI: 10.36185/2532-1900-031 -
Cancer Letters Feb 2018Angiogenesis is the natural and physiologic process of growing blood vessels from pre-existing ones. Pathological angiogenesis occurs when the precise balance of all the... (Review)
Review
Angiogenesis is the natural and physiologic process of growing blood vessels from pre-existing ones. Pathological angiogenesis occurs when the precise balance of all the molecular pathways that regulate angiogenesis is disrupted, and this process is a critical step in many diseases, including cancer. A limited number of antiangiogenic synthetic drugs have been developed. However, due to toxicity and side effects issues, the search for alternative to existing drugs is ongoing. In this sense, natural molecules obtained from plants or macrofungi, have demonstrated extraordinary potential in the treatment of angiogenesis-related pathologies, specially taking into consideration its absence or very low toxicity, when compared to synthetic drugs. Using natural compounds as potential angiogenesis modulators is thus a promising field of research, supporting the creation of novel therapies able to reduce the use of drugs and associated side effects. In this review, the current status of antiangiogenic drugs and the wide variety of natural extracts and molecules with antiangiogenic capacities, as well as the angiogenesis molecular pathways and therapeutic targets, are presented. Finally, the challenges that need to be overcome in order to increase the use of natural compounds for clinical purposes are discussed.
Topics: Angiogenesis Inhibitors; Biological Products; Fungi; Humans; Molecular Structure; Neoplasms; Neovascularization, Pathologic; Plants, Medicinal
PubMed: 29222042
DOI: 10.1016/j.canlet.2017.12.006 -
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 -
Acta Pharmacologica Sinica Oct 2015Angiogenesis, the formation of new blood vessels from the pre-existing vasculature is essential for embryonic development and tissue homeostasis. It also plays critical... (Review)
Review
Angiogenesis, the formation of new blood vessels from the pre-existing vasculature is essential for embryonic development and tissue homeostasis. It also plays critical roles in diseases such as cancer and retinopathy. A delicate balance between pro- and anti-angiogenic factors ensures normal physiological homeostasis. Endogenous angiogenesis inhibitors are proteins or protein fragments that are formed in the body and have the ability to limit angiogenesis. Many endogenous angiogenesis inhibitors have been discovered, and the list continues to grow. Endogenous protein/peptide inhibitors are relatively less toxic, better tolerated and have a lower risk of drug resistance, which makes them attractive as drug candidates. In this review, we highlight ten novel endogenous protein angiogenesis inhibitors discovered within the last five years, including ISM1, FKBPL, CHIP, ARHGAP18, MMRN2, SOCS3, TAp73, ZNF24, GPR56 and JWA. Although some of these proteins have been well characterized for other biological functions, we focus on their new and specific roles in angiogenesis inhibition and discuss their potential for therapeutic application.
Topics: Angiogenesis Inhibitors; Animals; Drug Discovery; Humans; Neoplasms; Neovascularization, Pathologic; Proteins
PubMed: 26364800
DOI: 10.1038/aps.2015.73 -
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 -
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