-
Clinical Science (London, England :... Sep 2020Over the past two decades, the treatment of cancer has been revolutionised by the highly successful introduction of novel molecular targeted therapies and... (Review)
Review
Over the past two decades, the treatment of cancer has been revolutionised by the highly successful introduction of novel molecular targeted therapies and immunotherapies, including small-molecule kinase inhibitors and monoclonal antibodies that target angiogenesis by inhibiting vascular endothelial growth factor (VEGF) signaling pathways. Despite their anti-angiogenic and anti-cancer benefits, the use of VEGF inhibitors (VEGFi) and other tyrosine kinase inhibitors (TKIs) has been hampered by potent vascular toxicities especially hypertension and thromboembolism. Molecular processes underlying VEGFi-induced vascular toxicities still remain unclear but inhibition of endothelial NO synthase (eNOS), reduced nitric oxide (NO) production, oxidative stress, activation of the endothelin system, and rarefaction have been implicated. However, the pathophysiological mechanisms still remain elusive and there is an urgent need to better understand exactly how anti-angiogenic drugs cause hypertension and other cardiovascular diseases (CVDs). This is especially important because VEGFi are increasingly being used in combination with other anti-cancer dugs, such as immunotherapies (immune checkpoint inhibitors (ICIs)), other TKIs, drugs that inhibit epigenetic processes (histone deacetylase (HDAC) inhibitor) and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, which may themselves induce cardiovascular injury. Here, we discuss vascular toxicities associated with TKIs, especially VEGFi, and provide an up-to-date overview on molecular mechanisms underlying VEGFi-induced vascular toxicity and cardiovascular sequelae. We also review the vascular effects of VEGFi when used in combination with other modern anti-cancer drugs.
Topics: Angiogenesis Inhibitors; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 32990313
DOI: 10.1042/CS20200308 -
Toxicology Aug 2021Oxaliplatin (OXA) is a third-generation platinum anticancer drug that is mainly used for the treatment of metastatic colorectal cancer (CRC). Of note, hepatic sinusoidal... (Review)
Review
Oxaliplatin (OXA) is a third-generation platinum anticancer drug that is mainly used for the treatment of metastatic colorectal cancer (CRC). Of note, hepatic sinusoidal obstruction syndrome (HSOS) induced by OXA has become a key concern for patients with CRC receiving chemotherapy with OXA in recent years. Splenomegaly, thrombocytopenia, abnormal liver function, and portal hypertension are some of the main clinical characteristics seen in patients with OXA-induced HSOS. Previous studies have suggested that oxidative stress, inflammatory damage, liver fibrosis, and platelet aggregation and adhesion may be involved in the pathogenesis of OXA-induced HSOS. Currently, there are no specific drugs for prevention and treatment of OXA-induced HSOS. In this review, we summarized the epidemiology, pathological characteristics, clinical predictive indicators, related mechanisms, possible prevention and treatment of OXA-related HSOS.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Hepatic Veno-Occlusive Disease; Humans; Oxaliplatin
PubMed: 34352347
DOI: 10.1016/j.tox.2021.152882 -
Cardiovascular Research Mar 2022Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth,... (Review)
Review
Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration, and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signalling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signalling pathway inhibition include an increase in arterial pressure, left ventricular dysfunction facilitating the development of heart failure, thromboembolic events including pulmonary embolism and stroke, and myocardial infarction. Sex steroids, such as androgens, progestins, and oestrogens and their receptors (ERα, ERβ, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor therapy, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target- and cell-type selectivity likely will open the way to personalized medicine in men and women requiring anti-angiogenic therapy to reduce adverse effects and to improve therapeutic efficacy.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Female; Humans; Male; Neovascularization, Pathologic; Sex Characteristics; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 33739385
DOI: 10.1093/cvr/cvab096 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Apr 2022Conventional therapies for malignant tumors have limitations and disadvantages. In recent years, the cancer starvation therapy has emerged which intends to deprive... (Review)
Review
Conventional therapies for malignant tumors have limitations and disadvantages. In recent years, the cancer starvation therapy has emerged which intends to deprive cancer cells of nutritional supply. There are several approaches to"starve" cancer cells: to intervene tumor angiogenesis by targeted inhibition of angiogenic factors or their receptors and integrins; to block the blood supply of cancer cells by embolizing or compressing blood vessels; to intervene metabolic process of cancer cells by inhibition of the signal pathways of mitochondrial serine-glycine-one earbon metabolism, glycolysis and amino acid metabolism; cancer starvation therapy can be employed with oxidation therapy, chemotherapy, sonodynamic therapy, anti-autophagy therapy or other therapies to achieve synergistic effects. This article reviews the research progress of cancer starvation therapy in recent years and discusses the existing problems.
Topics: Amino Acids; Angiogenesis Inhibitors; Glycine; Humans; Integrins; Neoplasms; Serine
PubMed: 35462463
DOI: 10.3724/zdxbyxb-2021-0297 -
Biomolecules Oct 2020Neovascular retinal degeneration is a leading cause of blindness in advanced countries. Anti-vascular endothelial growth factor (VEGF) drugs have been used for...
Neovascular retinal degeneration is a leading cause of blindness in advanced countries. Anti-vascular endothelial growth factor (VEGF) drugs have been used for neovascular retinal diseases; however, anti-VEGF drugs may cause the development of chorioretinal atrophy in chronic therapy as they affect the physiological amount of VEGF needed for retinal homeostasis. Hypoxia-inducible factor (HIF) is a transcription factor inducing VEGF expression under hypoxic and other stress conditions. Previously, we demonstrated that HIF was involved with pathological retinal angiogenesis in murine models of oxygen-induced retinopathy (OIR), and pharmacological HIF inhibition prevented retinal neovascularization by reducing an ectopic amount of VEGF. Along with this, we attempted to find novel effective HIF inhibitors. Compounds originally isolated from mushroom-forming fungi were screened for prospective HIF inhibitors utilizing cell lines of 3T3, ARPE-19 and 661W. A murine OIR model was used to examine the anti-angiogenic effects of the compounds. As a result, 2-azahypoxanthine (AHX) showed an inhibitory effect on HIF activation and suppressed mRNA upregulation under CoCl-induced pseudo-hypoxic conditions. Oral administration of AHX significantly suppressed retinal neovascular tufts in the OIR model. These data suggest that AHX could be a promising anti-angiogenic agent in retinal neovascularization by inhibiting HIF activation.
Topics: 3T3 Cells; Angiogenesis Inhibitors; Animals; Cell Hypoxia; Cobalt; Corneal Dystrophies, Hereditary; Disease Models, Animal; Gene Expression Regulation; Hypoxia-Inducible Factor 1; Mice; Retinal Neovascularization; Vascular Endothelial Growth Factor A
PubMed: 33020402
DOI: 10.3390/biom10101405 -
Current Oncology Reports Jul 2021Both anti-angiogenesis and immunotherapy are well-established therapeutic options in solid tumors. Here, we review the rationale as well as clinical evidence of... (Review)
Review
PURPOSE OF REVIEW
Both anti-angiogenesis and immunotherapy are well-established therapeutic options in solid tumors. Here, we review the rationale as well as clinical evidence of combining these two approaches.
RECENT FINDINGS
There is strong rationale and substantial preclinical and clinical evidence that anti-angiogenesis plays a pivotal role in overcoming immunotherapy resistance. The combination of an anti-angiogenic agent and a checkpoint inhibitor offers a more robust treatment option in many clinical trials in a wide variety of solid tumor types. Combination of anti-angiogenesis and immunotherapy has emerged as a standard of care in some tumor types and the indication is expected to expand to more tumor types in the years to come.
Topics: Angiogenesis Inhibitors; Animals; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Neovascularization, Pathologic; Outcome Assessment, Health Care; Survival Analysis; Tumor Microenvironment
PubMed: 34269922
DOI: 10.1007/s11912-021-01099-7 -
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 -
Methods in Molecular Biology (Clifton,... 2023The angiogenesis process was described in its basic concepts in the works of the Scottish surgeon John Hunter and terminologically assessed in the early twentieth...
The angiogenesis process was described in its basic concepts in the works of the Scottish surgeon John Hunter and terminologically assessed in the early twentieth century. An aberrant angiogenesis is a prerequisite for cancer cells in solid tumors to grow and metastasize. The sprouting of new blood vessels is one of the major characteristics of cancer and represents a gateway for tumor cells to enter both the blood and lymphatic circulation systems. In vivo, ex vivo, and in vitro models of angiogenesis have provided essential tools for cancer research and antiangiogenic drug screening. Several in vivo studies have been performed to investigate the various steps of tumor angiogenesis and in vitro experiments contributed to dissecting the molecular bases of this phenomenon. Moreover, coculture of cancer and endothelial cells in 2D and 3D matrices have contributed to improve the recapitulation of the complex process of tumor angiogenesis, including the peculiar conditions of tumor microenvironment.
Topics: Angiogenesis Inhibitors; Coculture Techniques; Endothelial Cells; Humans; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 36161404
DOI: 10.1007/978-1-0716-2703-7_1 -
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