-
221S-1a inhibits endothelial proliferation in pathological angiogenesis through ERK/c-Myc signaling.European Journal of Pharmacology Aug 2023Pathological angiogenesis plays a major role in many disease processes, including cancer and diabetic retinopathy. Antiangiogenic therapy is a potential management for...
Pathological angiogenesis plays a major role in many disease processes, including cancer and diabetic retinopathy. Antiangiogenic therapy is a potential management for pathologic angiogenesis. The novel synthetic compound 221S-1a, derived from captopril, tanshinol and borneol, may have antiangiogenic properties. On the basis of MS, NMR and HPLC analysis, the structure of 221S-1a was identified. The cellular uptake and metabolism of this compound was also observed. Next, the antiangiogenic properties of 221S-1a were evaluated in tumor-xenograft and OIR models in vivo. The inhibitory properties of 221S-1a on endothelial cell proliferation, migration, tube formation and sprouting were detected in vitro. Furthermore, 221S-1a induced G1/S phase arrest was detected by PI staining flow cytometry analysis and Cyclin D, Cyclin E expression. 221S-1a inhibited ERK1/2 activation and nuclear translocation, in addition to downregulation of c-Myc, a transcription factor that regulates cell cycle progression. Molecular docking indicated the interaction of 221S-1a with the ATP-binding site of ERK2, leading to the inhibition of ERK2 phosphorylation and a concomitant inhibition of ERK1 phosphorylation. In conclusion, 221S-1a inhibited the G1/S phase transition by blocking the ERK1/2/c-Myc pathway to reduce tumor and OIR retinal angiogenesis. These novel findings suggest that 221S-1a is a potential pharmacologic candidate for treating pathological angiogenesis.
Topics: Humans; Signal Transduction; Proto-Oncogene Proteins c-myc; Molecular Docking Simulation; Neovascularization, Pathologic; Cell Proliferation
PubMed: 37247812
DOI: 10.1016/j.ejphar.2023.175805 -
Cancer Letters Aug 2009Solid tumor malignancies including breast, lung and prostate carcinomas are considered to be angiogenesis dependent. Tumor angiogenesis is often mediated by hypoxia... (Review)
Review
Solid tumor malignancies including breast, lung and prostate carcinomas are considered to be angiogenesis dependent. Tumor angiogenesis is often mediated by hypoxia secondary to tumor growth or by increased oncogenic signaling. Both mechanisms result in increased hypoxia-inducible factor-1 alpha (HIF-1alpha) signaling and its transcriptional target vascular endothelial growth factor (VEGF). Critical to HIF-1alpha signaling are post translational modifications including acetylation mediated by histone acetyltransferases (HATS) and deacetylation by histone deacetylases (HDACs). More recently, HDACs were shown to be up-regulated in response to hypoxia mediating increased HIF-1alpha signaling. HDAC inhibitors represent a new class of anti-cancer therapeutics which show great promise at inhibiting angiogenesis in pre-clinical animal models and early phase clinical trials. This review will discuss the role of HIF-1alpha and VEGF influence on tumor angiogenesis and how HDACs play a critical role in HIF-1alpha transcriptional activity. Furthermore it will also be discussed how targeting HDACs via their inhibition create new avenues in treating solid malignancies by increasing the activity of established and novel therapeutic applications.
Topics: Acetylation; Angiogenesis Inhibitors; Animals; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Neovascularization, Pathologic; Transcription, Genetic; Vascular Endothelial Growth Factor A
PubMed: 19111391
DOI: 10.1016/j.canlet.2008.11.012 -
Biomedicine & Pharmacotherapy =... Sep 2023The antitumor effects of traditional drugs have received increasing attention and active antitumor components extracted from traditional drugs have shown good efficacy... (Review)
Review
The antitumor effects of traditional drugs have received increasing attention and active antitumor components extracted from traditional drugs have shown good efficacy with minimal adverse events. Cepharanthine(CEP for short) is an active component derived from the Stephania plants of Menispermaceae, which can regulate multiple signaling pathways alone or in combination with other therapeutic drugs to inhibit tumor cell proliferation, induce apoptosis, regulate autophagy, and inhibit angiogenesis, thereby inhibiting tumor progression. Therefore, we retrieved studies concerning CEP's antitumor effects in recent years and summarized the antitumor mechanism and targets, in order to gain new insights and establish a theoretical basis for further development and application of CEP.
Topics: Benzylisoquinolines; Benzodioxoles; Antineoplastic Agents; Cell Proliferation; Humans; Cell Line, Tumor; Apoptosis; Radiation Tolerance; Autophagy; Angiogenesis
PubMed: 37423171
DOI: 10.1016/j.biopha.2023.115107 -
Advanced Science (Weinheim,... Apr 2024Chronic diabetic wounds are a serious complication of diabetes and often result in limb amputations and confer high mortality rates. The proinflammatory secretome in the...
Chronic diabetic wounds are a serious complication of diabetes and often result in limb amputations and confer high mortality rates. The proinflammatory secretome in the wound perpetuates defective neovascularization and contributes to dysregulated tissue repair. This study aims to design a gelatin methacrylamide (GelMA) hydrogel to sustained the release of grancalcin-neutralizing antibody (GCA-NAb) and evaluate it as a potential scaffold to promote diabetic wound healing. Results show that the expression of grancalcin(GCA), a protein secreted by bone marrow-derived immune cells, is elevated in the wound sites of individuals and animals with diabetic ulcers. Genetic inhibition of grancalcin expression accelerates vascularization and healing in an animal model. Mechanistic studies show that grancalcin binds to transient receptor potential melastatin 8(TRPM8) and partially inactivates its downstream signaling pathways, thereby impairing angiogenesis in vitro and ex vivo. Systemic or topical administration of a GCA-NAb accelerate wound repair in mice with diabetes. The data suggest that GCA is a potential therapeutic target for the treatment of diabetic ulcers.
Topics: Animals; Mice; Angiogenesis; Diabetes Complications; Diabetes Mellitus; Neovascularization, Pathologic; Ulcer; Wound Healing; Calcium-Binding Proteins
PubMed: 38308197
DOI: 10.1002/advs.202305856 -
BMC Biology Apr 2023Angiogenesis plays important roles in physiological and pathologic conditions, but the mechanisms underlying this complex process often remain to be elucidated. In...
BACKGROUND
Angiogenesis plays important roles in physiological and pathologic conditions, but the mechanisms underlying this complex process often remain to be elucidated. In recent years, liquid-liquid phase separation (LLPS) has emerged as a new concept to explain many cellular functions and diseases. However, whether LLPS is involved in angiogenesis has not been studied until now. Here, we investigated the potential role of LLPS in angiogenesis and endothelial function.
RESULTS
We found 1,6-hexanediol (1,6-HD), an inhibitor of LLPS, but not 2,5-hexanediol (2,5-HD) dramatically decreases neovascularization of Matrigel plug and angiogenesis response of murine corneal in vivo. Moreover, 1,6-HD but not 2,5-HD inhibits microvessel outgrowth of aortic ring and endothelial network formation. The endothelial function of migration, proliferation, and cell growth is suppressed by 1,6-HD. Global transcriptional analysis by RNA-sequencing reveals that 1,6-HD specifically blocks cell cycle and downregulates cell cycle-related genes including cyclin A1. Further experimental data show that 1,6-HD treatment greatly reduces the expression of cyclin A1 but with minimal effect on cyclin D1, cyclin E1, CDK2, and CDK4. The inhibitory effect of 1,6-HD on cyclin A1 is mainly through transcriptional regulation because proteasome inhibitors fail to rescue its expression. Furthermore, overexpression of cyclin A1 in HUVECs largely rescues the dysregulated tube formation upon 1,6-HD treatment.
CONCLUSIONS
Our data reveal a critical role of LLPS inhibitor 1,6-HD in angiogenesis and endothelial function, which specifically affects endothelial G1/S transition through transcriptional suppression of CCNA1, implying LLPS as a possible novel player to modulate angiogenesis, and thus, it might represent an interesting therapeutic target to be investigated in clinic angiogenesis-related diseases in future.
Topics: Humans; Mice; Animals; Cyclin A1; Human Umbilical Vein Endothelial Cells; Cell Movement; Neovascularization, Pathologic; Cell Proliferation
PubMed: 37024934
DOI: 10.1186/s12915-023-01580-8 -
Open Biology Dec 2017Endothelial cell (EC) metabolism has lately emerged as a novel and promising therapeutic target to block vascular dysregulation associated with diseases like cancer and... (Review)
Review
Endothelial cell (EC) metabolism has lately emerged as a novel and promising therapeutic target to block vascular dysregulation associated with diseases like cancer and blinding eye disease. Glycolysis, fatty acid oxidation (FAO) and, more recently, glutamine/asparagine metabolism emerged as key regulators of EC metabolism, able to impact angiogenesis in health and disease. ECs are highly glycolytic as they require ATP and biomass for vessel sprouting. Notably, a regulator of the glycolytic pathway, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, controls vessel sprouting during the angiogenic switch and its inhibition in tumour ECs leads to vessel normalization, thereby reducing metastasis and ameliorating chemotherapy. Moreover, FAO promotes EC proliferation through DNA synthesis, and plays an essential role in lymphangiogenesis via epigenetic regulation of histone acetylation. Pathological angiogenesis was decreased upon blockade of carnitine palmitoyltransferase 1, a regulator of FAO in ECs. More recently, metabolism of glutamine, in conjunction with asparagine, was reported to maintain EC sprouting through TCA anaplerosis, redox homeostasis, mTOR activation and endoplasmic stress control. Inactivation or blockade of glutaminase 1, which hydrolyses glutamine into ammonia and glutamate, impairs angiogenesis in health and disease, while silencing of asparagine synthetase reduces vessel sprouting In this review, we summarize recent insights into EC metabolism and discuss therapeutic implications of targeting EC metabolism.
Topics: Animals; Antineoplastic Agents; Endothelium, Vascular; Energy Metabolism; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Oxidative Stress
PubMed: 29263247
DOI: 10.1098/rsob.170219 -
Journal of Atherosclerosis and... Jun 2018The structural and functional integrity of endothelium is essential for the maintenance of vascular health. Vasohibin-1 (VASH1), originally isolated as an... (Review)
Review
The structural and functional integrity of endothelium is essential for the maintenance of vascular health. Vasohibin-1 (VASH1), originally isolated as an endothelium-derived angiogenesis inhibitor, has another function to promote stress tolerance of endothelial cells (ECs), and these functions are critical for the maintenance of vascular homeostasis preventing both pathological angiogenesis and stress-induced vascular diseases. The expression of VASH1 is downregulated during replicative senescence of ECs by the alteration of microRNA expression, and this age-associated downregulation of VASH1 might be a risk of deterioration of vascular homeostasis and age-related vascular diseases. Contrary to this expectation, the lack of Vash1 gene in mice exhibited healthy longevity. Thus, VASH1 has double-face for the maintenance of vascular homeostasis and healthy longevity. This feature of VASH1 and its mechanism will be described in this mini review.
Topics: Cell Cycle Proteins; Endothelium, Vascular; Homeostasis; Humans; Longevity; Neovascularization, Physiologic
PubMed: 29398681
DOI: 10.5551/jat.43398 -
PloS One 2023Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type...
Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11β-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11β-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11β-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.
Topics: Mice; Female; Animals; Glucocorticoids; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Inflammation; Neovascularization, Pathologic; Neoplasms; Fibrosis
PubMed: 36940215
DOI: 10.1371/journal.pone.0255709 -
International Journal of Molecular... May 2021In this study, we report the effects of caffeine on angiogenesis in zebrafish embryos both during normal development and after exposure to Fibroblast Growth Factor 2...
In this study, we report the effects of caffeine on angiogenesis in zebrafish embryos both during normal development and after exposure to Fibroblast Growth Factor 2 (FGF2). As markers of angiogenesis, we measured the length and width of intersegmental vessels (ISVs), performed whole-mount in situ hybridization with and vascular markers, and counted the number of interconnecting vessels (ICVs) in sub-intestinal venous plexus (SIVP). In addition, we measured angiogenesis after performing zebrafish yolk membrane (ZFYM) assay with microinjection of fibroblast growth factor 2 (FGF2) and perivitelline tumor xenograft assay with microinjection of tumorigenic FGF2-overexpressing endothelial (FGF2-T-MAE) cells. The results showed that caffeine treatment causes a shortening and thinning of ISVs along with a decreased expression of the vascular marker genes and a decrease in the number of ICVs in the SIVP. Caffeine was also able to block angiogenesis induced by exogenous FGF2 or FGF2-producing cells. Overall, our results are suggestive of the inhibitory effect of caffeine in both direct and indirect angiogenesis.
Topics: Animals; Caffeine; Cell Line, Tumor; Embryo, Nonmammalian; Embryonic Development; Fibroblast Growth Factor 2; Gene Expression Regulation, Developmental; Heterografts; Humans; In Situ Hybridization; Neovascularization, Pathologic; Neovascularization, Physiologic; Zebrafish
PubMed: 34063734
DOI: 10.3390/ijms22094856 -
World Journal of Gastroenterology Nov 2006Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating... (Review)
Review
Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of anti-angiogenesis therapy. Transfer of anti-angiogenesis genes has received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy.
Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Genetic Therapy; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 17109514
DOI: 10.3748/wjg.v12.i43.6941