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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 -
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 -
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 -
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 -
Journal of Hematology & Oncology Oct 2016Monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) directed against the vascular endothelial growth factor (VEGF) or its receptors have been... (Meta-Analysis)
Meta-Analysis Review
Monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) directed against the vascular endothelial growth factor (VEGF) or its receptors have been investigated in several studies for the treatment of advanced gastric cancer (GC). In the present study, we aimed to evaluate the efficacy and safety of angiogenesis inhibitors in advanced GC. We searched published randomized controlled trials (RCTs) comparing angiogenesis inhibitors with non-angiogenesis inhibitors for the treatment of GC. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched. The extracted data on progression-free survival (PFS) and overall survival (OS) were measured in terms of hazard ratios (HR) and corresponding 95 % confidence intervals (CIs). In addition, risk ratios (RR) and corresponding 95 % CIs were pooled for objective response rate (ORR), disease control rate (DCR), and risk of adverse events (AEs). Ten RCTs involving 2786 patients were included. Compared with non-angiogenesis inhibitor-containing regimens, angiogenesis inhibitor-containing regimens resulted in a significant improvement in OS (HR 0.80, 95 % CI 0.69-0.93, P = 0.004), prolonged PFS (HR 0.66, 95 % CI 0.51-0.86, P = 0.002), and superior ORR (RR 1.34, 95 % CI 1.09-1.65, P = 0.005) and DCR (RR 1.37, 95 % CI 1.17-1.61, P = 0.0001). Angiogenesis inhibitors were associated with a greater number of AEs, but most of these were predictable and manageable. However, hand-foot syndrome, diarrhea, and gastrointestinal (GI) perforation were significantly increased in patients treated with angiogenesis inhibitors. In summary, angiogenesis inhibitor-containing regimens were superior to non-angiogenesis inhibitor-containing regimens in terms of OS, PFS, RR, and DCR in patients with advanced GC.
Topics: Angiogenesis Inhibitors; Disease-Free Survival; Humans; Randomized Controlled Trials as Topic; Stomach Neoplasms; Survival Rate; Treatment Outcome
PubMed: 27756337
DOI: 10.1186/s13045-016-0340-8 -
International Journal of Molecular... May 2015Epidemiological studies have revealed that high consumption of soy products is associated with low incidences of hormone-dependent cancers, including breast and prostate... (Review)
Review
Epidemiological studies have revealed that high consumption of soy products is associated with low incidences of hormone-dependent cancers, including breast and prostate cancer. Soybeans contain large amounts of isoflavones, such as the genistein and daidzain. Previously, it has been demonstrated that genistein, one of the predominant soy isoflavones, can inhibit several steps involved in carcinogenesis. It is suggested that genistein possesses pleiotropic molecular mechanisms of action including inhibition of tyrosine kinases, DNA topoisomerase II, 5α-reductase, galectin-induced G2/M arrest, protein histidine kinase, and cyclin-dependent kinases, modulation of different signaling pathways associated with the growth of cancer cells (e.g., NF-κB, Akt, MAPK), etc. Moreover, genistein is also a potent inhibitor of angiogenesis. Uncontrolled angiogenesis is considered as a key step in cancer growth, invasion, and metastasis. Genistein was found to inhibit angiogenesis through regulation of multiple pathways, such as regulation of VEGF, MMPs, EGFR expressions and NF-κB, PI3-K/Akt, ERK1/2 signaling pathways, thereby causing strong antiangiogenic effects. This review focuses on the antiangiogenic properties of soy isoflavonoids and examines their possible underlying mechanisms.
Topics: Angiogenesis Inhibitors; Animals; Breast; Breast Neoplasms; Female; Genistein; Humans; Isoflavones; Neovascularization, Pathologic; Signal Transduction; Glycine max
PubMed: 26006245
DOI: 10.3390/ijms160511728 -
Current Oncology Reports Apr 2022While vascular endothelial growth factor receptor inhibitors (VEGFRis) have dramatically improved cancer survival, these drugs cause hypertension in a majority of... (Review)
Review
PURPOSE OF REVIEW
While vascular endothelial growth factor receptor inhibitors (VEGFRis) have dramatically improved cancer survival, these drugs cause hypertension in a majority of patients. This side effect is often dose limiting and increases cardiovascular mortality in cancer survivors. This review summarizes recent advances in our understanding of the molecular mechanisms and clinical findings that impact management of VEGFRi-induced hypertension.
RECENT FINDINGS
Recent studies define new connections between endothelial dysfunction and VEGFRi-induced hypertension, including the balance between nitric oxide, oxidative stress, endothelin signaling, and prostaglandins and the potential role of microparticles, vascular smooth muscle cells, vascular stiffness, and microvessel rarefaction. Data implicating genetic polymorphisms that might identify patients at risk for VEGFRi-induced hypertension and the growing body of literature associating VEGFRi-induced hypertension with antitumor efficacy are reviewed. These recent advances have implications for the future of cardio-oncology clinics and the management of VEGFRi-induced hypertension.
Topics: Angiogenesis Inhibitors; Humans; Hypertension; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 35179707
DOI: 10.1007/s11912-022-01224-0 -
Oxidative Medicine and Cellular... 2019Alkaloids are among the natural phytochemicals contained in functional foods and nutraceuticals and have been suggested for the prevention and/or management of oxidative... (Review)
Review
Alkaloids are among the natural phytochemicals contained in functional foods and nutraceuticals and have been suggested for the prevention and/or management of oxidative stress and inflammation-mediated diseases. In this review, we aimed to describe the effects of alkaloids in angiogenesis, the process playing a crucial role in tumor growth and invasion, whereby new vessels form. Antiangiogenic compounds including herbal ingredients, nonherbal alkaloids, and microRNAs can be used for the control and treatment of cancers. Several lines of evidence indicate that alkaloid-rich plants have several interesting features that effectively inhibit angiogenesis. In this review, we present valuable data on commonly used alkaloid substances as potential angiogenic inhibitors. Different herbal and nonherbal ingredients, introduced as antiangiogenesis agents, and their role in angiogenesis-dependent diseases are reviewed. Studies indicate that angiogenesis suppression is exerted through several mechanisms; however, further investigations are required to elucidate their precise molecular and cellular mechanisms, as well as potential side effects.
Topics: Alkaloids; Angiogenesis Inhibitors; Humans
PubMed: 31178979
DOI: 10.1155/2019/9475908 -
Gynecologic Oncology Mar 2023Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial...
OBJECTIVE
Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts.
METHODS
mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial.
RESULTS
The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment.
CONCLUSIONS
Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials.
Topics: Humans; Female; Bevacizumab; Vascular Endothelial Growth Factor A; Angiogenesis Inhibitors; Retrospective Studies; Prospective Studies; Ovarian Neoplasms; Neovascularization, Pathologic; Prognosis
PubMed: 36758419
DOI: 10.1016/j.ygyno.2023.01.034