ABSTRACT
BACKGROUND: Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. OBJECTIVE: This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. FINDINGS: Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1ß (IL-ß), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor ß1 (TGF-ß1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1ß, IL-6, TNF-α, VEGF, TGFß, and MMPs in different animal models of diseases. CONCLUSION: It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.
Subject(s)
Cannabidiol , Endometriosis , Inflammation , Neovascularization, Pathologic , Endometriosis/drug therapy , Endometriosis/pathology , Female , Humans , Cannabidiol/therapeutic use , Cannabidiol/pharmacology , Neovascularization, Pathologic/drug therapy , Inflammation/drug therapy , Animals , Cytokines/metabolism , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/pharmacology , AngiogenesisABSTRACT
This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm3 murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5-20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5-100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice.
Subject(s)
Dose Fractionation, Radiation , Animals , Mice , Female , Stilbenes/pharmacology , Stilbenes/administration & dosage , Mice, Inbred C3H , Neovascularization, Pathologic/radiotherapy , Neovascularization, Pathologic/drug therapy , Cell Line, Tumor , Mammary Neoplasms, Experimental/radiotherapy , Mammary Neoplasms, Experimental/blood supply , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathologyABSTRACT
Insufficient angiogenic stimulation and dysregulated glycolipid metabolism in senescent vascular endothelial cells (VECs) constitute crucial features of vascular aging. Concomitantly, the generation of excess senescence-associated secretory phenotype (SASP) and active immune-inflammatory responses propagates within injured vessels, tissues, and organs. Until now, targeted therapies that efficiently rectify phenotypic abnormalities in senescent VECs have still been lacking. Here, we constructed a Pd/hCeO2-BMS309403@platelet membrane (PCBP) nanoheterostructured capsule system loaded with fatty acid-binding protein 4 (FABP4) inhibitors and modified with platelet membranes and investigated its therapeutic role in aged mice. PCBP showed significant maintenance in aged organs and demonstrated excellent biocompatibility. Through cyclic tail vein administration, PCBP extended the lifespan and steadily ameliorated abnormal phenotypes in aged mice, including SASP production, immune and inflammatory status, and age-related metabolic disorders. In senescent ECs, PCBP mediated the activation of vascular endothelial growth factor (VEGF) signaling and glycolysis and inhibition of FABP4 by inducing the synthesis of hypoxia-inducible factor-1α, thereby reawakening neovascularization and restoring glycolipid metabolic homeostasis. In conclusion, the PCBP nanocapsule system provides a promising avenue for interventions against aging-induced dysfunction.
Subject(s)
Aging , Nanocapsules , Animals , Mice , Aging/metabolism , Nanocapsules/chemistry , Humans , Mice, Inbred C57BL , Glycolipids/chemistry , Glycolipids/metabolism , Cellular Senescence/drug effects , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , AngiogenesisABSTRACT
Multiple myeloma (MM) is a neoplastic condition resulting from the uncontrolled expansion of B-cell-derived plasma cells. The importance of angiogenesis in MM development has also been demonstrated. Extracellular vesicles (EVs) have vital functions in interactions between neighboring cells, such as angiogenesis. The objective of this in vitro study was to examine the transfection and angiogenesis effects of MM-EVs on endothelial cells (ECs) upon treatment with Tetrahydroisoquinoline (THIQ) as a bioactive organic compound derivative from isoquinoline. Following treatment of multiple myeloma cells (U266) with THIQ, MM-EVs were harvested and transmigrated to human umbilical vein endothelial cells (HUVEC) in a co-culture model. EVs transmigration was traced by flow cytometry. Correspondingly, the expression of angiogenic genes and/or proteins in U266 cells and HUVECs was measured by RT-PCR and ELISA methods. Likewise, the proliferation and migration of HUVECs treated with THIQ-treated MM-EVs were visualized and estimated by performing both tube formation and scratch wound healing methods. Surprisingly, the anti-angiogenic effect of THIQ-treated MM-EVs was evident by the decreased expression of CD34, VEGFR2, and IL-6 at the mRNA and/or protein levels after internalization of MM-EVs in HUVEC. Finally, tube formation and scratch wound healing experiments showed inhibition of HUVEC cell proliferation and migration by THIQ-treated MM-EVs compared to control MM-EVs. MM-EVs derived from THIQ-treated myeloma cells (U266) inhibited angiogenesis in HUVECs. This phenomenon is coordinated by the internalized THIQ-treated MM-EVs in HUVECs, and ultimately the reduction of angiogenic factors and inhibition of tube formation and scratch wound healing.
Subject(s)
Cell Movement , Extracellular Vesicles , Human Umbilical Vein Endothelial Cells , Multiple Myeloma , Neovascularization, Pathologic , Tetrahydroisoquinolines , Humans , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Multiple Myeloma/pathology , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Extracellular Vesicles/metabolism , Extracellular Vesicles/drug effects , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/metabolism , Tetrahydroisoquinolines/pharmacology , Cell Movement/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Coculture Techniques , Angiogenesis Inhibitors/pharmacology , AngiogenesisABSTRACT
This review explores the pivotal role of angiogenesis in breast cancer progression and treatment. It covers biomarkers, imaging techniques, therapeutic approaches, resistance mechanisms, and clinical implications. Key topics include Vascular Endothelial Growth Factors, angiopoietins, microRNA signatures, and circulating endothelial cells as biomarkers, along with Magnetic Resonance Imaging, Computed Tomography Angiography, Ultrasound, and Positron Emission Tomography for imaging. Therapeutic strategies targeting VEGF, tyrosine kinase inhibitors, and the intersection of angiogenesis with immunotherapy are discussed. Challenges such as resistance mechanisms and personalized medicine approaches are addressed. Clinical implications, prognostic value, and the future direction of angiogenesis-targeted therapies are highlighted. The article concludes with reflections on the transformative potential of understanding angiogenesis.
Subject(s)
Breast Neoplasms , Neovascularization, Pathologic , Female , Humans , Angiogenesis/drug effects , Angiogenesis/physiopathology , Angiogenesis Inhibitors/therapeutic use , Breast Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/physiopathologyABSTRACT
Background: Osteosarcoma is the most common malignant primary bone tumor. The prognosis for patients with disseminated disease remains very poor despite recent advancements in chemotherapy. Moreover, current treatment regimens bear a significant risk of serious side effects. Thus, there is an unmet clinical need for effective therapies with improved safety profiles. Taurolidine is an antibacterial agent that has been shown to induce cell death in different types of cancer cell lines. Methods: In this study, we examined both the antineoplastic and antiangiogenic effects of taurolidine in animal models of osteosarcoma. K7M2 murine osteosarcoma cells were injected, both intramuscular and intraperitoneal, into 60 BALB/c mice on day zero. Animals were then randomized to receive treatment with taurolidine 2% (800 mg/kg), taurolidine 1% (400 mg/kg), or NaCl 0.9% control for seven days by intravenous or intraperitoneal administration. Results: After 35 days, mice were euthanized, and the tumors were harvested for analysis. Eighteen mice were excluded from the analysis due to complications. Body weight was significantly lower in the 2% taurolidine intraperitoneal treatment group from day 9 to 21, consistent with elevated mortality in this group. Intraperitoneal tumor weight was significantly lower in the 1% (p = 0.003) and 2% (p = 0.006) intraperitoneal taurolidine treatment groups compared to the control. No antineoplastic effects were observed on intramuscular tumors or for intravenous administration of taurolidine. There were no significant differences in microvessel density or mitotic rate between treatment groups. Reduced body weight and elevated mortality in the 2% taurolidine intraperitoneal group suggest that the lower 1% dose is preferable. Conclusions: In conclusion, there is no evidence of antiangiogenic activity, and the antitumor effects of taurolidine on osteosarcoma observed in this study are limited. Moreover, its toxic profile grants further evaluation. Given these observations, further research is necessary to refine the use of taurolidine in osteosarcoma treatment.
Subject(s)
Bone Neoplasms , Disease Models, Animal , Osteosarcoma , Taurine , Thiadiazines , Tumor Burden , Animals , Taurine/analogs & derivatives , Taurine/pharmacology , Taurine/therapeutic use , Thiadiazines/pharmacology , Thiadiazines/therapeutic use , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Osteosarcoma/blood supply , Mice , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Tumor Burden/drug effects , Microvascular Density/drug effects , Mice, Inbred BALB C , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Humans , Neovascularization, Pathologic/drug therapyABSTRACT
Rationale: Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and unsatisfactory efficacy remain issues. The identification of novel targets for anti-angiogenic treatment is still needed. Methods: We investigated the role of tsRNA-1599 in ocular angiogenesis using endothelial cells, a streptozotocin (STZ)-induced diabetic model, a laser-induced choroidal neovascularization model, and an oxygen-induced retinopathy model. CCK-8 assays, EdU assays, transwell assays, and matrigel assays were performed to assess the role of tsRNA-1599 in endothelial cells. Retinal digestion assays, Isolectin B4 (IB4) staining, and choroidal sprouting assays were conducted to evaluate the role of tsRNA-1599 in ocular angiogenesis. Transcriptomic analysis, metabolic analysis, RNA pull-down assays, and mass spectrometry were utilized to elucidate the mechanism underlying angiogenic effects mediated by tsRNA-1599. Results: tsRNA-1599 expression was up-regulated in experimental ocular angiogenesis models and endothelial cells in response to angiogenic stress. Silencing of tsRNA-1599 suppressed angiogenic effects in endothelial cells in vitro and inhibited pathological ocular angiogenesis in vivo. Mechanistically, tsRNA-1599 exhibited little effect on VEGF signaling but could cause reduced glycolysis and NAD+/NADH production in endothelial cells by regulating the expression of HK2 gene through interacting with YBX1, thus affecting endothelial effects. Conclusions: Targeting glycolytic reprogramming of endothelial cells by a tRNA-derived small RNA represents an exploitable therapeutic approach for ocular neovascular diseases.
Subject(s)
Choroidal Neovascularization , Endothelial Cells , Glycolysis , Animals , Glycolysis/drug effects , Mice , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Choroidal Neovascularization/drug therapy , Choroidal Neovascularization/metabolism , Humans , Y-Box-Binding Protein 1/metabolism , Y-Box-Binding Protein 1/genetics , Angiogenesis Inhibitors/pharmacology , Hexokinase/metabolism , Hexokinase/genetics , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Mice, Inbred C57BL , Male , Disease Models, Animal , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Diabetic Retinopathy/drug therapy , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/genetics , Human Umbilical Vein Endothelial Cells , RNA, Small Untranslated/genetics , RNA, Small Untranslated/metabolismABSTRACT
Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.
Subject(s)
Drug Combinations , Drug Synergism , Gastrointestinal Neoplasms , Mutation , Neoplastic Stem Cells , Neovascularization, Pathologic , Phenylurea Compounds , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins p21(ras) , Pyridines , Pyrrolidines , STAT3 Transcription Factor , Thymine , Trifluridine , Uracil , Xenograft Model Antitumor Assays , Humans , Trifluridine/pharmacology , Phenylurea Compounds/pharmacology , Animals , Pyridines/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Gastrointestinal Neoplasms/metabolism , Uracil/pharmacology , Uracil/analogs & derivatives , Mice , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Thymine/pharmacology , Cell Line, Tumor , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , MAP Kinase Signaling System/drug effects , Signal Transduction/drug effects , Cell Proliferation/drug effects , AngiogenesisABSTRACT
Angiogenesis, the formation of new blood vessels, stimulates tumor growth and spread by delivering oxygen and nutrients, and is a key component of metastasis. This work aimed to evaluate the anti-angiogenic properties of a new synthesized compound. Rat aorta angiogenesis assay was used to evaluate the ability of the carbothioamide derivative to inhibit blood vessels sprouting. The tetrazolium (MTT) assay was used to evaluate the anti-proliferative effect of the synthetic compound on human umbilical vein endothelial cell line (HUVECs) and A549 lung cancer cells line. The (2, 2-diphenyl-1-picrylhydrazyl) DPPH was used to investigate the free radical scavenging action. The study showed that the compound has anti-angiogenic activity with IC50 56.9 µg/mL, moreover the compound managed to inhibit the proliferation of HUVECs and A549 cells (IC50 76.3 µg/mL and 45.5 µg/mL, respectively), and The IC50 concentration for free radical scavenging activity of the compound was 27.8 µg/ml. The study concluded that the compound has significant anti-angiogenic activity may be related to its significant anti-proliferative effect against HUVECs, these pharmacological effect may attributed to its potent free radical scavenging activity.
Subject(s)
Angiogenesis Inhibitors , Cell Proliferation , Human Umbilical Vein Endothelial Cells , Humans , Cell Proliferation/drug effects , Rats , Angiogenesis Inhibitors/pharmacology , Animals , Human Umbilical Vein Endothelial Cells/drug effects , A549 Cells , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Antineoplastic Agents/pharmacology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Hydrazines/pharmacology , Thioamides/pharmacology , Thioamides/chemistry , MaleABSTRACT
A literature search was conducted to review papers on the results of studies of clear cell renal cancer (CCRC) vascularization. Numerous data on the relationship between tumor pathogenesis and its vascularization have been revealed, which indicates the multifactorial nature of CCRC development and the significant role of angiogenesis in this process. It should be taken into account that patients with CCRC may have impaired vessel formation even before tumor development. To evaluate normal and pathologic angiogenesis, a pathohistologic study using immunohistochemistry is certainly necessary. Due to the significant role of angiogenesis in the development and course of CCRC, the use of drugs that suppress the formation of the vascular network in the tumor is relevant and advisable. To date, many drugs have been developed and introduced into clinical practice to inhibit angiogenesis. However, such drugs have not lived up to the expectations placed due to the frequent and rapidly developing drug resistance. Timely detection of pre-tumor and tumor processes, as well as effective treatment of cancer, including CCRC, is possible only with close cooperation between pathomorphologists and oncologists.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Neovascularization, Pathologic , Humans , Kidney Neoplasms/pathology , Kidney Neoplasms/blood supply , Kidney Neoplasms/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/drug therapy , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/drug therapy , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/pharmacology , AngiogenesisABSTRACT
BACKGROUND/AIM: Most clear cell renal cell carcinomas (ccRCCs) have a dysfunctional von Hippel-Lindau tumor suppressor protein (VHL). Hypoxia-inducible factors 1 and 2 alpha (HIF1α and HIF2α) accumulate in ccRCC with dysfunctional VHL and up-regulate the vascular endothelial growth factor (VEGF) pathway and tumor angiogenesis. Recently, pimitespib (PIM), a potent ATP-competitive inhibitor of heat shock protein 90 (HSP90), was developed. PIM down-regulates the expression of HIF, a key protein in ccRCC progression, with anti-angiogenic effects. This study aimed to examine the effectiveness of PIM in ccRCC and the underlying mechanisms. MATERIALS AND METHODS: The efficacy and mechanism of PIM against ccRCCs was evaluated using ccRCC cell lines. RESULTS: PIM inhibited the VEGFR pathway by down-regulating VEGFR 2, phosphorylated VEGFR 2, and protein levels in downstream signaling pathways. The growth of ccRCC cell lines was inhibited by PIM. Furthermore, PIM inhibits HIF1α, HIF2α, and VEGF expression, suggesting that PIM may suppress angiogenesis in addition to the VEGFR pathway. CONCLUSION: PIM provides a novel approach for treating ccRCC and holds promise for future clinical strategies. Further in vivo and clinical research is required to elucidate the detailed relationship between the effects of PIM and ccRCC.
Subject(s)
Carcinoma, Renal Cell , HSP90 Heat-Shock Proteins , Kidney Neoplasms , Neovascularization, Pathologic , Signal Transduction , Humans , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Signal Transduction/drug effects , Cell Line, Tumor , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Neovascularization, Pathologic/drug therapy , Cell Proliferation/drug effects , Angiogenesis Inhibitors/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Gene Expression Regulation, Neoplastic/drug effects , TriazolesABSTRACT
Glioma cells overexpress different peptide receptors that are useful for research, diagnosis, management, and treatment of the disease. Oncogenic peptides favor the proliferation, migration, and invasion of glioma cells, as well as angiogenesis, whereas anticancer peptides exert antiproliferative, antimigration, and anti-angiogenic effects against gliomas. Other peptides exert a dual effect on gliomas, that is, both proliferative and antiproliferative actions. Peptidergic systems are therapeutic targets, as peptide receptor antagonists/peptides or peptide receptor agonists can be administered to treat gliomas. Other anticancer strategies exerting beneficial effects against gliomas are discussed herein, and future research lines to be developed for gliomas are also suggested. Despite the large amount of data supporting the involvement of peptides in glioma progression, no anticancer drugs targeting peptidergic systems are currently available in clinical practice to treat gliomas.
Subject(s)
Antineoplastic Agents , Glioma , Peptides , Humans , Glioma/drug therapy , Glioma/metabolism , Glioma/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Peptides/pharmacology , Peptides/therapeutic use , Animals , Receptors, Peptide/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Proliferation/drug effects , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolismABSTRACT
Angiogenesis is a physiological process of forming new blood vessels that has pathological importance in seemingly unrelated illnesses like cancer, diabetes, and various inflammatory diseases. Treatment targeting angiogenesis has shown promise for these types of diseases, but current anti-angiogenic agents have critical limitations in delivery and side-effects. This necessitates exploration of alternative approaches like biomolecule-based drugs. Proteins, lipids, and oligonucleotides have recently become popular in biomedicine, specifically as biocompatible components of therapeutic drugs. Their excellent bioavailability and potential bioactive and immunogenic properties make them prime candidates for drug discovery or drug delivery systems. Lipid-based liposomes have become standard vehicles for targeted nanoparticle (NP) delivery, while protein and nucleotide NPs show promise for environment-sensitive delivery as smart NPs. Their therapeutic applications have initially been hampered by short circulation times and difficulty of fabrication but recent developments in nanofabrication and NP engineering have found ways to circumvent these disadvantages, vastly improving the practicality of biomolecular NPs. In this review, we are going to briefly discuss how biomolecule-based NPs have improved anti-angiogenesis-based therapy.
Subject(s)
Angiogenesis Inhibitors , Neovascularization, Pathologic , Theranostic Nanomedicine , Humans , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/administration & dosage , Theranostic Nanomedicine/methods , Neovascularization, Pathologic/drug therapy , Animals , Liposomes/chemistry , Nanostructures/chemistry , Neoplasms/drug therapy , Drug Delivery Systems/methods , Oligonucleotides/chemistry , Oligonucleotides/administration & dosage , Oligonucleotides/pharmacokinetics , Oligonucleotides/pharmacology , Proteins/chemistry , Proteins/administration & dosage , Lipids/chemistry , Nanoparticles/chemistryABSTRACT
Lignans, a class of secondary metabolites found in plants, along with their derivatives, exhibit diverse pharmacological activities, including antioxidant, antimicrobial, anti-inflammatory, and antiangiogenic ones. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process for cancer growth and development. Several studies have elucidated the synergistic relationship between angiogenesis and inflammation in various inflammatory diseases, highlighting a correlation between inflammation and vascular endothelial growth factor (VEGF)-induced angiogenesis. Thus, the identification of novel molecules capable of modulating VEGF effects presents promising prospects for developing therapies aimed at stabilizing, reversing, or even arresting disease progression. Lignans often suffer from low aqueous solubility and, for their use, encapsulation in a delivery system is needed. In this research, a bioinspired benzoxantene has been encapsulated in solid lipid nanoparticles that have been characterized for their pharmacotechnical properties and their thermotropic behavior. The effects of these encapsulated nanoparticles on angiogenic parameters and inflammation in VEGF-induced angiogenesis were evaluated using human brain microvascular endothelial cells (HBMECs) as a human blood-brain barrier model.
Subject(s)
Blood-Brain Barrier , Inflammation , Nanoparticles , Vascular Endothelial Growth Factor A , Humans , Nanoparticles/chemistry , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Vascular Endothelial Growth Factor A/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Lipids/chemistry , Neovascularization, Physiologic/drug effects , Angiogenesis , LiposomesABSTRACT
Malignant melanoma presents a formidable challenge due to its aggressive metastatic behavior and limited response to current treatments. To address this, our study delves into the impact of anlotinib on angiogenesis and vasculogenic mimicry using malignant melanoma cells and human umbilical vein endothelial cells. Evaluating tubular structure formation, cell proliferation, migration, invasion, and key signaling molecules in angiogenesis, we demonstrated that anlotinib exerts a dose-dependent inhibition on tubular structures and effectively suppresses cell growth and invasion in both cell types. Furthermore, in a mouse xenograft model, anlotinib treatment resulted in reduced tumor growth and vascular density. Notably, the downregulation of VEGFR-2, FGFR-1, PDGFR-ß, and PI3K underscored the multitargeted antitumor activity of anlotinib. Our findings emphasize the therapeutic potential of anlotinib in targeting angiogenesis and vasculogenic mimicry, contributing to the development of novel strategies for combating malignant melanoma.
Subject(s)
Cell Movement , Cell Proliferation , Human Umbilical Vein Endothelial Cells , Indoles , Melanoma , Neovascularization, Pathologic , Quinolines , Vascular Endothelial Growth Factor Receptor-2 , Xenograft Model Antitumor Assays , Quinolines/pharmacology , Quinolines/therapeutic use , Quinolines/administration & dosage , Humans , Melanoma/drug therapy , Melanoma/pathology , Animals , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Indoles/pharmacology , Indoles/therapeutic use , Mice , Cell Proliferation/drug effects , Cell Line, Tumor , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Cell Movement/drug effects , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Signal Transduction/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/therapeutic use , Receptor, Platelet-Derived Growth Factor beta/metabolism , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Mice, Nude , AngiogenesisABSTRACT
BACKGROUND: Vascular Endothelial Growth Factor Receptors (VEGFR1 and VEGFR2) are tyrosine kinase receptors expressed on endothelial cells and tumor vessels and play an important role in angiogenesis. In this study, three repeats of VEGFR1 and VEGFR2 binding peptide (VGB3) were genetically fused to the truncated diphtheria toxin (TDT), and its in vitro activity was evaluated. METHODS: The recombinant construct (TDT-triVGB3) was expressed in bacteria cells and purified with nickel affinity chromatography. The binding capacity and affinity of TDT-triVGB3 were evaluated using the enzyme-linked immunosorbent assay. The inhibitory activity of TDT-triVGB3 on viability, migration, and tube formation of human endothelial cells was evaluated using MTT, migration, and tube formation assays. RESULTS: TDT-triVGB3 selectively detected VEGFR1 and VEGFR2 with high affinity in an enzyme- linked immunosorbent assay and significantly inhibited viability, migration, and tube formation of human endothelial cells. CONCLUSION: The developed TDT-triVGB3 is potentially a novel agent for targeting VEGFR1/ VEGFR2 over-expressing cancer cells.
Subject(s)
Angiogenesis Inhibitors , Cell Movement , Diphtheria Toxin , Human Umbilical Vein Endothelial Cells , Vascular Endothelial Growth Factor Receptor-1 , Vascular Endothelial Growth Factor Receptor-2 , Humans , Vascular Endothelial Growth Factor Receptor-1/genetics , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism , Diphtheria Toxin/genetics , Diphtheria Toxin/pharmacology , Diphtheria Toxin/metabolism , Cell Movement/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/genetics , Angiogenesis Inhibitors/chemistry , Cell Survival/drug effects , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/pharmacology , Recombinant Fusion Proteins/metabolism , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/drug therapy , Gene Expression , Endothelial Cells/metabolism , Endothelial Cells/drug effectsABSTRACT
It is acknowledged that conventional renal cell carcinoma (cRCC), which makes up 85% of renal malignancies, is a highly vascular tumor. Humanized monoclonal antibodies were developed to inhibit tumor neo-angiogenesis, which is driven by VEGFA/KDR signaling. The results largely met our expectations, and in several cases, adverse events occurred. Our study aimed to analyze the expression of VEGFA and its receptor KDR by immunohistochemistry in tissue multi-array containing 811 cRCC and find a correlation between VEGFA/KDR signaling and new vessel formation. None of the 811 cRCC displayed VEGFA-positive immunostaining. However, each glomerulus in normal kidney showed VEGFA-positive endothelial cells. KDR expression in endothelial meshwork was found in only 9% of cRCC, whereas 2% of the cRCC displayed positive KDR reaction in the cytoplasm of tumor cells. Our results disclose the involvement of VEGFA/KDR signaling in the neo-vascularization of cRCC and explain the frequent resistance to drugs targeting the VEGFA/KDR signaling and the high frequency of adverse events.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Signal Transduction , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor Receptor-2 , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Humans , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Female , Male , Middle Aged , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/drug therapy , Aged , Molecular Targeted Therapy , AdultABSTRACT
Melanoma is the most aggressive form of skin cancer and originates from genetic mutations in melanocytes. The disease is multifactorial, but its main cause is overexposure to UV radiation. Currently, available chemotherapy expresses little to no results, which may justify the extensive use of natural products to treat this cancer. In this study, we reviewed the inhibition of melanoma angiogenesis by natural products and its potential mechanisms using literature from PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases. According to summarizes 27 natural products including alkaloids, polyphenols, terpenoids, flavonoids, and steroids that effectively inhibit angiogenesis in melanoma. In addition to these there are 15 crude extracts that can be used as promising agents to inhibit angiogenesis, but their core components still deserve further investigation. There are current studies on melanoma angiogenesis involving oxidative stress, immune-inflammatory response, cell proliferation and migration and capillary formation. The above natural products can be involved in melanoma angiogenesis through core targets such as VE-cadherin, COX-2, iNOS, VEGF, bFGF, FGF2,MMP2,MMP9,IL-1ß,IL-6 play a role in inhibiting melanoma angiogenesis. Effective excavation of natural products can not only clarify the mechanism of drug action and key targets, but also help to promote the preclinical research of natural products for melanoma treatment and further promote the development of new clinical drugs, which will bring the gospel to the vast number of patients who are deeply afflicted by melanoma.
Subject(s)
Angiogenesis Inhibitors , Biological Products , Melanoma , Neovascularization, Pathologic , Skin Neoplasms , Melanoma/drug therapy , Melanoma/blood supply , Humans , Biological Products/pharmacology , Neovascularization, Pathologic/drug therapy , Skin Neoplasms/drug therapy , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , AngiogenesisABSTRACT
Treatment of patients with locally advanced rectal cancer (RC) is based on neoadjuvant chemoradiotherapy followed by surgery. In order to reduce the development of therapy resistance, it is necessary to further improve previous treatment approaches. Recent in vivo experimental studies suggested that the reduction of tumor hypoxia by tumor vessel normalization (TVN), through the inhibition of the glycolytic activator PFKFB3, could significantly improve tumor response to therapy. We have evaluated in vitro and in vivo the effects of the PFKFB3 inhibitor 2E-3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) on cell survival, clonogenicity, migration, invasion, and metabolism using colorectal cancer cells, patient-derived tumor organoid (PDO), and xenograft (PDX). 3PO treatment of colorectal cancer cells increased radiation-induced cell death and reduced cancer cell invasion. Moreover, gene set enrichment analysis shows that 3PO is able to alter the metabolic status of PDOs toward oxidative phosphorylation. Additionally, in vivo neoadjuvant treatment with 3PO induced TVN, alleviated tumor hypoxia, and increased tumor necrosis. Our results support PFKFB3 inhibition as a possible future neoadjuvant addition for patients with RC. SIGNIFICANCE: Novel therapies to better treat colorectal cancer are necessary to improve patient outcomes. Therefore, in this study, we evaluated the combination of a metabolic inhibitor (3PO) and standard radiotherapy in different experimental settings. We have observed that the addition of 3PO increased radiation effects, ultimately improving tumor cell response to therapy.
Subject(s)
Phosphofructokinase-2 , Rectal Neoplasms , Xenograft Model Antitumor Assays , Phosphofructokinase-2/antagonists & inhibitors , Phosphofructokinase-2/metabolism , Phosphofructokinase-2/genetics , Humans , Animals , Rectal Neoplasms/pathology , Rectal Neoplasms/radiotherapy , Rectal Neoplasms/drug therapy , Rectal Neoplasms/metabolism , Mice , Cell Line, Tumor , Pyridines/pharmacology , Pyridines/therapeutic use , Necrosis , Tumor Hypoxia/drug effects , Neoadjuvant Therapy/methods , Neovascularization, Pathologic/drug therapyABSTRACT
In the last years, 5-pyrazolyl ureas and 5-aminopyrazoles have been investigated for their antiangiogenetic properties and their potential interaction with the ubiquitous Ca2+ binding protein Calreticulin. Based on the structure of the active compounds I and GeGe-3, novel 5-arylamino pyrazoles 2 and 3 were synthesized through a stepwise procedure. In MTT assays, all the new derivatives proved to be non-cytotoxic against eight different tumor cell lines, normal fibroblasts, and endothelial cells. Furthermore, selected derivatives showed relevant antiangiogenetic properties, resulting more effective than reference molecules I and GeGe-3 in inhibiting HUVEC endothelial tube formation. 5-Arylamino pyrazoles 2a and 2d were identified as the most interesting compounds and significantly prevented tube formation of tumor secretome-stimulated HUVEC. Furthermore, the two compounds inhibited HUVEC migration in wound healing assay and altered cell invasion capability. Additionally, 2a and 2d strongly affected Ca2+ mobilization and cytoskeletal organization of HUVEC cells, being as active as the reference compound GeGe-3. Differently from previous studies, molecular docking simulations suggested a poor affinity of 2a towards Calreticulin, one of the interacting partners of the lead compound GeGe-3. Collectively, this new amino-pyrazole library further extends the structure-activity relationships of the previously prepared derivatives and confirmed the biological attractiveness of this chemical scaffold as antiangiogenetic agents.