Prevention Of Angiogenesis Research Articles

A MgAl-LDH-CuS nanosheet-based thermo-responsive composite hydrogel with nir-responsive angiogenesis inhibitor releasing capability for multimode starvation therapy

The rapid proliferation of tumors is highly dependent on the nutrition supply of blood vessels. Cutting off the nutrient supply to tumors is an effective strategy for cancer treatment, known as starvation therapy. Although various hydrogel-based biomaterials have been developed for starvation therapy through glucose consumption or intravascular embolization, the limitations of single-mode starvation therapy hinder their therapeutic effects. Herein, we propose a dual-function nutrition deprivation strategy that can block the nutrients delivery through extravascular gelation shrinkage and inhibit neovascularization through angiogenesis inhibitors based on a novel NIR-responsive nanocomposite hydrogel. CuS nanodots-modified MgAl-LDH nanosheets loaded with angiogenesis inhibitor (sorafenib, SOR) are incorporated into the poly(n-isopropylacrylamide) (PNIPAAm) hydrogel by radical polymerization to obtain the composite hydrogel (SOR@LDH-CuS/P). The SOR@LDH-CuS/P hydrogel can deliver hydrophobic SOR with a NIR-responsive release behavior, which could decrease the tumor vascular density and accelerate cancer cells apoptosis. Moreover, the SOR@LDH-CuS/P hydrogel exhibits higher (3.5 times) compressive strength than that of the PNIPAAm, which could squeeze blood vessels through extravascular gelation shrinkage. In vitro and in vivo assays demonstrate that the interruption of nutrient supply by gelation shrinkage and the prevention of angiogenesis by SOR is a promising strategy to inhibit tumor growth for multimode starvation therapy.

<p>Inhibition of the hedgehog pathway for the treatment of cancer using Itraconazole</p>

Itraconazole (ITZ) is an anti-fungal drug that has been used in clinical practice for nearly 35 years. Recently, numerous experiments have shown that ITZ possesses anti-cancer properties. The Hedgehog (Hh) pathway plays a pivotal role in fundamental processes, including embryogenesis, structure, morphology and proliferation in various species. This pathway is typically silent in adult cells, and inappropriate activity is linked to various tumor types. The most important mechanism of ITZ in the treatment of cancer is inhibition of the Hh pathway through the inhibition of smoothened receptors (SMO), glioma-associated oncogene homologs (GLI), and their downstream targets. In this review, we discuss the mechanisms of ITZ in the treatment of cancer through inhibition of the Hh pathway, which includes anti-inflammation, prevention of tumor growth, induction of cell cycle arrest, induction of apoptosis and autophagy, prevention of angiogenesis, and drug resistance. We also discuss the clinical use of ITZ in many types of cancers. We hope this review will provide more information to support future studies on ITZ in the treatment of various cancers.

Repurposing itraconazole for the treatment of cancer.

The repurposing of drugs is becoming increasingly attractive as it avoids the lengthy process and cost implications associated with bringing a novel drug to market. Itraconazole is a broad-spectrum anti-fungal agent. An emerging body of in vivo, in vitro and clinical evidence have confirmed that it also possesses antineoplastic activities and has a synergistic action when combined with other chemotherapeutic agents. It acts via several mechanisms to prevent tumour growth, including inhibition of the Hedgehog pathway, prevention of angiogenesis, decreased endothelial cell proliferation, cell cycle arrest and induction of auto-phagocytosis. These allow itraconazole, either alone or in combination with other cytotoxic agents, to increase drug efficacy and overcome drug resistance. This study reviews the reported literature on the use of itraconazole in a variety of malignancies and highlights the recent insights into the critical pathways acted upon to prevent tumour growth.

Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis.

Angiogenesis plays a critical role in the growth and metastasis of cancer, and growth factors released from cancer promote blood-vessel formation in the tumor microenvironment. The angiogenesis is accelerated via interactions of growth factors with the high-affinity receptors on cancer cells. In particular, heparan sulfate proteoglycans (HSPGs) on the surface of cancer cells have been shown to be important in many aspects of determining a tumor’s phenotype and development. Specifically, the regulation of the interactions between HSPGs and growth factors results in changes in tumor progression. A peptide with heparin-binding (HBP) activity has been developed and synthesized to inhibit tumor growth via the prevention of angiogenesis. We hypothesized that HBP could inhibit the interaction of growth factors and HSPGs on the surface of cancer cells, decrease paracrine signaling in endothelial cells (ECs), and finally decrease angiogenesis in the tumor microenvironment. In this study, we found that HBP had antiangiogenic effects in vitro and in vivo. The conditioned media obtained from a breast cancer cell line treated with HBP were used to culture human umbilical vein ECs (HUVECs) to evaluate the antiangiogenic effect of HBP on ECs. HBP effectively inhibited the migration, invasion, and tube formation of HUVECs in vitro. In addition, the expressions of angiogenesis-mediating factors, including ERK, FAK, and Akt, were considerably decreased. HBP also decreased the levels of invasive factors, including MMP2 and MMP9, secreted by the HUVECs. We demonstrated significant suppression of tumor growth in a breast cancer xenograft model and enhanced distribution of HBP at the site of tumors. Taken together, our results show that HBP has antiangiogenic effects on ECs, and suggest that it may serve as a potential antitumor agent through control of the tumor microenvironment.

Regulation of Hypoxia-inducible Factor-1α and Vascular Endothelial Growth Factor Signaling by Plant Flavonoids.

Discovery of novel drugs that are able to prevent angiogenesis is a fast growing branch of cancer research. Current approaches to cancer chemotherapy include the use of alkylating agents, antimetabolites, antitumor antibiotics, platinum analogs and drugs derived from natural compounds. However, most of the currently used chemotherapeutic drugs have adverse side effects on normal healthy cells. In addition to the classical targets of cancer chemotherapy, prevention of angiogenesis through the regulation of indigenous angiogenic factors is a leading approach of developing selective novel anticancer drugs. Because of their low toxicity, there is increasing interest in exploring specific dietary phytochemicals as possible antiangiogenic agents. In this mini-review, selected flavonoids (e.g., apigenin, luteolin, quercetin and epigallocatechin-3-gallate, which are a group of plant polyphenols) that are able to regulate angiogenesis in in vitro and in vivo systems are discussed in the light of their potential to be exploited as novel anticancer drugs.

SL1122-37, a novel derivative of sorafenib, has greater effects than sorafenib on the inhibition of human hepatocellular carcinoma (HCC) growth and prevention of angiogenesis

SL1122-37 is a novel derivative of sorafenib that was characterized by introducing trifluoromethyl on the 4-position of indazole. We aimed to evaluate the effects of SL1122- 37 on human hepatocellular carcinoma (HCC) growth and on umbilical vein vascular endothelial cells (HUVECs) angiogenesis. Its efficacy and mechanisms were compared with sorafenib. SL1122-37 significantly prevented PLC/PRF/5 cell proliferation as estimated by colorimetric assay. Flow cytometry analysis showed the induction of apoptosis and arrest of cell cycle in G1 phase. Western blotting showed the decrease of cyclin D1 and regulation of apoptotic proteins. Further analysis suggested that these effects of SL1122-37 might arise from its roles in the inhibition of multi-kinases, including c-Kit and its downstream targets and the Wnt/β-catenin pathway in PLC/PRF/5 cells. SL1122-37 also possessed the activity of antiangiogenesis, showing the prevention of HUVEC migration and capillary tube formation. Western blotting indicated the inhibition of VEGF and phosphorylation of VEGFR-2 in HUVECs. Statistical analysis suggested that SL1122-37 might possess greater activities than sorafenib in the prevention of HCC proliferation and HUVEC angiogenesis. Conclusion, SL1122-37 could develop as a potent anticancer agent for the treatment of HCC.

Targeting Angiogenesis for Controlling Neuroblastoma

Neuroblastoma, a progressive solid tumor in childhood, continues to be a clinical challenge. It is highly vascular, heterogeneous, and extracranial tumor that originates from neural crest. Angiogenesis, genetic abnormalities, and oncogene amplification are mainly responsible for malignant phenotype of this tumor. Survivability of malignant neuroblastoma patients remains poor despite the use of traditional therapeutic strategies. Angiogenesis is a very common and necessary pre-requisite for tumor progression and metastasis. Angiogenesis is also a major factor in making malignant neuroblastoma. Thus, prevention of angiogenesis can be a highly significant strategy in the treatment of malignant neuroblastoma. Here, we summarize our current understanding of angiogenesis in malignant neuroblstoma and describe the use of experimental anti-angiogenic agents either alone or in combination therapy. This review will clearly indicate the importance of angiogenesis in the pathogenesis of malignant neuroblastoma, its prevention as a promising therapy in preclinical models of malignant neuroblastoma, and prospective clinical trials.

Abstract 4188: Association of HOX gene expression with osteopontin in ovarian cancer: Implications for biomarker development

Abstract Ovarian cancer is characterized by poor early detection and serves as an excellent model system to develop potential markers for early diagnosis. Osteopontin is a glycophosphoprotein known to demonstrate multiple functions including mediation of cellular adhesion, suppression of macrophage interleukin production, prevention of angiogenesis, apoptosis, and inhibition of anchorage-dependent growth. Studies of Osteopontin in ovarian cancer have described increased expression and a role as a candidate biomarker. Secretion of Osteopontin into the extra cellular matrix is reported to facilitate metastasis and has been reported to be inhibited by the presence of cytoplasmic Homeobox proteins (HOX). The HOX family of genes encodes transcription factors involved in basic developmental processes and has been linked to oncogenesis. Dysregulation of HOX genes may be an early event in malignant transformation making the HOX gene family appealing for biomarker investigation. In this study we characterize HOX gene expression in malignant tumors of the ovary compared to Osteopontin, a known biomarker for ovarian cancer. Methods: Microarray analysis of mRNA from human ovarian tissues was performed on samples of normal, benign, and malignant ovarian tissues. These samples were analyzed using the Affymetrix Human Genome Focus GeneChip (HG-Focus) microarray to distinguish the differential pattern of mRNA expression between the three types of samples. Immunohistochemistry staining of ovarian tissue samples was utilized to analyze confirmatory protein expression of the microarray findings. Results: Microarray analysis demonstrated up-regulation of HOXB2, HOXB7, and Osteopontin genes in malignant ovarian tumor samples compared to normal ovarian tissue controls. Conversely, HOXC6 was down-regulated in malignant tissue samples. Immunohistochemistry was performed for HOXB2, HOXC6 and Osteopontin on OCT embedded tissues samples. Similarly, increased protein expression was shown for HOXB2 and Osteopontin in malignant samples and increased HOXC6 in non-cancerous samples. Conclusion: Our results demonstrate multiple HOX genes to be up-regulated in ovarian cancer. Increased expression of HOXB2 and HOXB7, correlated with increased Osteopontin expression found in malignant ovarian tissue samples. HOXC6 demonstrated an inverse relationship with Osteopontin in non-cancerous ovarian tissue samples. The association of these HOX genes with Osteopontin expression warrants further investigation into the role of HOX genes as candidate biomarkers for ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4188. doi:10.1158/1538-7445.AM2011-4188

Abstract 1384: Prevention of angiogenesis by aldose reductase inhibition

Abstract We have recently shown that Aldose Reductase (AR) known to be involved in oxidative stress-signaling, initiated by inflammatory markers, prevents human colon cancer cell growth in culture as well as in nude mice xenografts. Inhibition of AR also prevents azoxymethane-induced aberrant crypt foci formation in mice. In order to understand the chemopreventive mechanism of AR inhibition in colon cancer, we have investigated the role of AR in the mediation of angiogenic signals in vitro and in vivo models. Using human umbilical vein endothelial cells (HUVEC), we have investigated the effect of AR inhibition on VEGF- and bFGF- induced tube as well as spheroid formation in in vitro angiogenesis. We have also determined the invasion and migration of HUVEC by inhibition of AR. Further, to determine the in vivo efficacy of AR inhibition on angiogenesis, matrigel plug assay was performed using a rat model. Our results show that inhibition of AR significantly prevented the VEGF- and bFGF -induced proliferation and generation of reactive oxygen species in HUVEC. Further, AR inhibition also prevented the VEGF- and bFGF- induced secretion/expression of IL-6, MMP1, MMP9, ICAM, and VCAM. Matrigel plug model of angiogenesis in rats showed that inhibition of AR prevented the infiltration of blood cells, invasion, migration and formation of capillary like structures, and expression of blood vessels markers CD31 and vWF. Thus, our results demonstrate that AR inhibitors could be novel drugs for cancer chemoprevention by inhibiting angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1384.

Fighting Cancer with Red Wine? Molecular Mechanisms of Resveratrol

Resveratrol, a red wine constituent, has been known for its cardioprotective effects. Recent data give ample evidence that resveratrol can act as a chemopreventive agent as well. Tumor initation, promotion, and progression are affected by resveratrol via multiple pathways, which are discussed in this review. Resveratrol has anti-inflammatory effects by counteracting NF-κ B and AP-1 transcription and can prevent bioactivation of procarcinogens by interacting with drug metabolizing enzymes. Furthermore, resveratrol exerts antioxidant activities, hence contributing to the prevention of tumor initiation. Growing or metastasizing carcinomas are inhibited by resveratrol through prevention of angiogenesis by inhibiting VEGF and matrix metalloproteases. Induction of apoptosis and cell cycle arrest, important mechanisms for cancer therapy, are stimulated by resveratrol through different mechanisms, e.g., activation of p53 and modulation of cell cycle proteins. Although there has been remarkable evidence for resveratrol as a potent chemopreventive agent in vitro, it seems that the low bioavailability of resveratrol in humans could interfere with a successful in vivo treatment. Nevertheless, resveratrol offers two major advantages over conventional chemotherapy. The cytotoxic effects of resveratrol on healthy cells can be neglected, and, as several pathways leading to chemotherapeutic effects are activated by resveratrol, chemoresistance-inducing mutations in cancer cells can be overcome.

Tumor Cell Plasticity in Ewing Sarcoma, an Alternative Circulatory System Stimulated by Hypoxia

A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis.

A mathematical model of tumour angiogenesis, regulated by vascular endothelial growth factor and the angiopoietins

Angiogenesis—the growth of new blood vessels from existing ones—is a prerequisite for the growth of solid tumours beyond a diameter of approximately 2 mm . In recent years, the angiopoietins have emerged as important regulators of angiogenesis. They mediate a delicate balance between vascular quiescence, regression and new growth, but their mechanism of action is not fully understood. This work attempts to provide a mathematical description of the role of the angiopoietins in angiogenesis. The model is formulated within the framework of reinforced random walks, which allows easy transition between the continuum (macroscopic) and discrete (microscopic) forms. Model predictions are in qualitative agreement with experimental observations, and may have implications for anti-cancer therapies based on the prevention of angiogenesis.

Gene therapy of lung cancer.

It is estimated that there will be 157,200 deaths from lung cancer in 2003. Current regimens of surgery, chemotherapy and radiation have not significantly changed overall 5-year survival rates for this disease. Thanks to intensive molecular studies over the last three decades, new targets for treatment have been identified, including replacement of tumor suppressor genes, prevention of angiogenesis and tumor growth, and regulation of programmed cell death. Promising advances have been made but obstacles still abound before effective use of these strategies at the patient bedside can occur. One area of concentration lies in developing more accurate and complete delivery of the therapeutic constructs. In the evolution of gene therapy approaches, from beginning theory to translational research, investigators in thoracic malignancies have played a leading role, utilizing a number of methods and delivery vehicles. The objective of this review is to discuss some of the major molecular targets available for manipulation in lung cancer, describe vectors and techniques currently used by thoracic researchers to deliver therapy, and provide the p53 model as an example of progression from bench research to clinical treatment.

Microencapsulation of an anti-VE-cadherin antibody secreting 1B5 hybridoma cells.

Accumulating experimental evidence demonstrates that tumor growth and lethality are dependent on angiogenesis. Based on this concept, there is growing interest in the use of antiangiogenesis agents to inhibit tumor expansion. Compelling data implicate vascular endothelium (VE)-cadherin (an endothelium specific protein) as a key factor in the last step of angiogenesis, where the endothelial cells join one to each other and form microtubules (future blood vessels). We propose a novel approach to the inhibition of angiogenesis by immobilizing VE-cadherin-secreting hybridoma cells in alginate-agarose microcapsules. Hybridoma cells can be protected with biocompatible and semipermeable membranes that permit exit of anti-VE-cadherin monoclonal antibodies but not entry of cellular immune mediators. Stability studies were performed to select the suitable microcapsule for cell immobilization. Alginate and agarose solid beads coated with poly-L-lysine and alginate were chosen according to their stability and diffusional properties. 1B5 hybridoma cells were grown within the microcapsules and secreted anti-VE-cadherin antibodies during the 9 days of culture, reaching a cumulative concentration of 1.7 microg/mL. This antibody concentration inhibited microtubule formation (87%) in the in vitro angiogenesis Matrigel assay. Moreover, the antiangiogenic effect observed was antibody concentration related. These findings open a new alternative for the inhibition or prevention of angiogenesis and demonstrates the feasibility of using microencapsulated cells as a control-drug delivery system.

COX-2 inhibition, apoptosis, and chemoprevention by nonsteroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) have as their common mechanism the inhibition of cyclooxygenase (COX) enzymes, of which two isoforms (COX-1 and COX-2) exist. The effect of NSAIDs on chemoprevention and tumor regression has been shown in animal models, epidemiologic studies, and in treatment of patients. The exact biochemical and cellular mechanisms underlying each of these phenomena is only partially understood. Processes that have been recently implicated as being important include the inhibition of tumor cell growth, prevention of angiogenesis, and induction of apoptosis in neoplastic cells.

Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by interleukin-10

AbstractBecause of its immunosuppressive properties, interleukin-10 (IL-10) is thought to play an important role in a number of human disease states, including inflammation, autoimmunity, and transplant rejection. In this study, we demonstrate that introduction of human or viral IL-10 genes into Burkitt's lymphoma cells markedly reduced their ability to grow as subcutaneous (sc) tumors in SCID mice. In vivo assays for angiogenesis revealed an inhibition of the angiogenic capacity of the IL-10–transfected lines. Recombinant human IL-10 abolished and viral IL-10 reduced vascular endothelial growth factor (VEGF)-165–induced neovascularization. Furthermore, IL-10 blocked the VEGF- and fibroblast growth factor (FGF)-2–induced proliferation of microvascular endothelial cells in vitro. The current observations suggest a direct role for IL-10 in the prevention of angiogenesis in human lymphoid malignancies.

Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by interleukin-10

Because of its immunosuppressive properties, interleukin-10 (IL-10) is thought to play an important role in a number of human disease states, including inflammation, autoimmunity, and transplant rejection. In this study, we demonstrate that introduction of human or viral IL-10 genes into Burkitt's lymphoma cells markedly reduced their ability to grow as subcutaneous (sc) tumors in SCID mice. In vivo assays for angiogenesis revealed an inhibition of the angiogenic capacity of the IL-10-transfected lines. Recombinant human IL-10 abolished and viral IL-10 reduced vascular endothelial growth factor (VEGF)-165-induced neovascularization. Furthermore, IL-10 blocked the VEGF- and fibroblast growth factor (FGF)-2-induced proliferation of microvascular endothelial cells in vitro. The current observations suggest a direct role for IL-10 in the prevention of angiogenesis in human lymphoid malignancies.

Inhibition by vasoactive intestinal polypeptide (VIP) of angiogenesis induced by murine Colon 26-L5 carcinoma cells metastasized in liver.

We investigated the effect of VIP on the liver metastases and angiogenesis by Colon 26-L5 carcinoma cells in mice. Daily systemic administration of VIP, beginning 3 days after tumor inoculation into a portal vein of mice, inhibited significantly the development of their liver metastases. Immunohistochemical staining for factor VIII-related antigen in the sections of liver metastases showed that the systemic administration of VIP caused significant prevention of angiogenesis within tumor masses. VIP (10-(10) to 10(-6) M) inhibited the invasion of reconstituted basement membrane (Matrigel) by hepatic sinusoidal endothelial (HSE) cells in a concentration-dependent manner in a Transwell chamber assay in vitro and achieved approximately 50% reduction of control at 10(-6) M. VIP (10(-6) M) also significantly suppressed the haptotactic migration of HSE cells to fibronectin, laminin or type I collagen substrates with a similar inhibition rate to the invasion assay. Exposure of VIP to HSE cells induced accumulation of intracellular cAMP in a concentration-dependent manner. The inhibitory effect of VIP (10(-6) M) on HSE cell migration was significantly abrogated in the presence of 3 x 10(-6) M H-89, a cAMP-dependent protein kinase inhibitor. VIP (10(-6) M) inhibited the morphogenesis of HSE cells into capillary-like structures on Matrigel-coated wells. VIP did not affect the proliferation of HSE cells and the production of gelatinases in HSE cells in vitro at the concentrations used in the invasion assay. These observations suggest that the anti-metastatic effect of VIP on liver metastases by Colon 26-L5 carcinoma cells in mice is partly due to the prevention of tumor angiogenesis probably through suppression of the motility of endothelial cells.