Cholesterol Trafficking: An Emerging Therapeutic Target for Angiogenesis and Cancer

Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, recent evidence suggests that cholesterol plays a key role in regulating angiogenesis. This review discusses the role of cholesterol in angiogenesis, with a particular emphasis on cholesterol trafficking in endothelial cell signaling. Small molecule inhibitors of cholesterol trafficking and their preclinical and clinical development targeting angiogenesis and cancer are also discussed.

• Publication year

  2019

• Venue

  Cells

• Publication date

  2019-04-28

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3390/cells8050389PMID 31035320PMCID 6562524
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking

  2018influential reference
• Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.

  2017influential reference
• The anti-cancer effects of itraconazole in epithelial ovarian cancer

  2017cited by this paper
• Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis.

  2017cited by this paper
• Tumor Progression of Non-Small Cell Lung Cancer Controlled by Albumin and Micellar Nanoparticles of Itraconazole, a Multitarget Angiogenesis Inhibitor.

  2017cited by this paper
• Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole

  2016cited by this paper
• Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism.

  2015influential reference
• Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection

  2015cited by this paper
• Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-line or Additional Setting.

  2015cited by this paper
• Lipid rafts as major platforms for signaling regulation in cancer.

  2015cited by this paper
• Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma.

  2014cited by this paper
• Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer.

  2013cited by this paper
• Control of Angiogenesis by AIBP-mediated Cholesterol Efflux

  2013cited by this paper
• Phase 2 Study of Pemetrexed and Itraconazole as Second-Line Therapy for Metastatic Nonsquamous Non–Small-Cell Lung Cancer

  2013cited by this paper
• Liver X Receptor Activation Reduces Angiogenesis by Impairing Lipid Raft Localization and Signaling of Vascular Endothelial Growth Factor Receptor-2

  2012cited by this paper
• Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer.

  2011cited by this paper
• Lipid rafts modulate the activation but not the maintenance of store-operated Ca(2+) entry.

  2010cited by this paper
• Cholesterol trafficking is required for mTOR activation in endothelial cells

  2010influential reference
• [Cepharanthin effect on radiation-induced xerostomia and taste disorder in patients with head and neck cancer].

  2009cited by this paper
• Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol.

  2009influential reference
• Restoration of lysosomal pH in RPE cells from cultured human and ABCA4(-/-) mice: pharmacologic approaches and functional recovery.

  2008cited by this paper
• Lipid Rafts Determine Clustering of STIM1 in Endoplasmic Reticulum-Plasma Membrane Junctions and Regulation of Store-operated Ca2+ Entry (SOCE)*

  2008cited by this paper
• Cellular cholesterol trafficking and compartmentalization

  2008influential reference
• Inhibition of angiogenesis by the antifungal drug itraconazole.

  2007cited by this paper
• Liver X receptors as integrators of metabolic and inflammatory signaling.

  2006cited by this paper
• Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia.

  2006cited by this paper
• The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).

  2005cited by this paper
• Role of cholesterol and lipid organization in disease

  2005cited by this paper
• [Effect of Cepharanthin in preventing radiation induced normal tissue damage in prostate cancer].

  2004cited by this paper
• Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport.

  2004cited by this paper
• SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.

  2002cited by this paper
• Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER.

  2002cited by this paper
• Statins Have Biphasic Effects on Angiogenesis

  2002cited by this paper
• ERRATA

  2001cited by this paper
• Inhibition of endothelial cell migration by cerivastatin, an HMG‐CoA reductase inhibitor: contribution to its anti‐angiogenic effect

  2001cited by this paper
• The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.

  2000cited by this paper
• Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models.

  2000cited by this paper
• Cholesterol depletion disrupts lipid rafts and modulates the activity of multiple signaling pathways in T lymphocytes

  2000cited by this paper
• Cholesterol in signal transduction.

  2000cited by this paper
• Topological Analysis of Niemann-Pick C1 Protein Reveals That the Membrane Orientation of the Putative Sterol-sensing Domain Is Identical to Those of 3-Hydroxy-3-methylglutaryl-CoA Reductase and Sterol Regulatory Element Binding Protein Cleavage-activating Protein*

  2000cited by this paper
• Lovastatin and tumor necrosis factor‐α exhibit potentiated antitumor effects against Ha‐ras‐transformed murine tumor Via inhibition of tumor‐induced angiogenesis

  1999cited by this paper
• A microscopic interaction model of maximum solubility of cholesterol in lipid bilayers.

  1999cited by this paper
• Tamoxifen inhibits acidification in cells independent of the estrogen receptor.

  1999cited by this paper
• Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types.

  1997cited by this paper
• Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.

  1997cited by this paper
• Molecular physiology of reverse cholesterol transport.

  1995cited by this paper
• Tamoxifen enhances cell death in implanted MCF7 breast cancer by inhibiting endothelium growth.

  1994cited by this paper
• Inhibition of angiogenesis by antiestrogens.

  1993cited by this paper
• Induction of Transforming Growth Factor β by the Antiestrogens Droloxifene, Tamoxifen, and Toremifene in MCF‐7 Cells

  1991cited by this paper
• Cholesterol transport between cells and high-density lipoproteins.

  1991cited by this paper
• Long-term adjuvant tamoxifen therapy for breast cancer

  1990cited by this paper
• Endocrine pharmacology of antiestrogens as antitumor agents.

  1990cited by this paper
• Clinical effects of cepharanthin (Ceph.) on leukopenia by chemotherapy in lung cancer patients.

  1989cited by this paper
• Potentiation of antitumor activity of vincristine by the biscoclaurine alkaloid cepharanthine.

  1987cited by this paper
• A receptor-mediated pathway for cholesterol homeostasis.

  1986cited by this paper
• Low Density Lipoprotein Metabolism by Endothelial Cells from Human Umbilical Cord Arteries and Veins

  1983cited by this paper
• The biological synthesis of cholesterol.

  1965cited by this paper
• Biological synthesis of cholesterol.

  1965cited by this paper
• Tumorigenesis and Neoplastic Progression Ezetimibe Is an Inhibitor of Tumor Angiogenesis

  year unknowncited by this paper

• Targeting Pathways Implicated in Cholesterol Metabolism for Novel Cancer Therapy

  2026cites this paper
• The Contribution of Cholesterol and Squalene Synthase in Cancer: Molecular Mechanisms, Lipid Rafts and Therapeutic Approaches

  2025cites this paper
• Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.

  2025cites this paper
• A primer on metabolic contributions in tumor angiogenic microenvironment.

  2025cites this paper
• Intracellular cholesterol: new functions and therapeutic approaches in NSCLC EGFR-TKI resistance

  2025cites this paper
• The effects of lysolecithin on gonadal development and growth performance of giant river prawn, Macrobrachium rosenbergii

  2025cites this paper
• Roles of Circadian Clocks in Macrophage Metabolism: Implications in Inflammation, and Metabolism of Lipids, Glucose, and Amino Acids.

  2025cites this paper
• Ternary Complex Components Responsible for Rapid LDL Internalization as Biomarkers for Breast Cancer Associated with Proliferation and Early Recurrence

  2025cites this paper
• Epigenetic drug screening identifies enzyme inhibitors A-196 and TMP-269 as novel regulators of sprouting angiogenesis

  2025cites this paper
• Cholesterol metabolism: A strategy for overcoming drug resistance in tumors.

  2025cites this paper
• Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish

  2024cites this paper
• The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting

  2024cites this paper
• Nanoparticle Targeting in Chemo‐Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance

  2024cites this paper
• Functional omics of ORP7 in primary endothelial cells

  2024cites this paper
• Two NPC1 homologous proteins are involved in asexual reproduction, pathogenicity, and lipid trafficking in Phytophthora sojae.

  2024cites this paper
• Cupric Doping Hollow Prussian Blue Nanoplatform for Enhanced Cholesterol Depletion: a Promising Strategy for Breast Cancer Therapy and Metastasis Inhibition

  2024cites this paper
• Cholesterol‐Conjugated PAMAM Dendrimers: Enhancing Stability, Drug Delivery Efficiency, and In Vitro Anticancer Performance

  2024cites this paper
• Exogenous estrogen partially rescues progesterone deficiency and autophagosome enlargement in Mcoln1−/− mouse model with lysosomal storage disorder

  2024cites this paper
• Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers

  2024cites this paper
• Endothelial Cells Mediated by STING Regulate Oligodendrogenesis and Myelination During Brain Development

  2024cites this paper
• A conjoint analysis of renal structure and omics characteristics reveal new insight to yak high-altitude hypoxia adaptation.

  2024cites this paper
• Association between Time-Weighted Remnant Cholesterol and Incident Cancer: A Population-Based Chinese Cohort Study

  2024cites this paper
• Carbon dots efficiently promote vascularization for enhanced repairing of orthopedic diseases with diabetic mellitus based on nanocatalytic medicine

  2023cites this paper
• M6PR- and EphB4-Rich Exosomes Secreted by Serglycin-Overexpressing Esophageal Cancer Cells Promote Cancer Progression

  2023cites this paper
• Cholesterol metabolism: Towards a therapeutic approach for multiple sclerosis.

  2023cites this paper
• Machine learning-based prediction of cerebral hemorrhage in patients with hemodialysis: A multicenter, retrospective study

  2023cites this paper
• The role of lipid rafts in vesicle formation.

  2023cites this paper
• Systemwide effects of ER-intracellular membrane contact site disturbance in primary endothelial cells.

  2023cites this paper
• Integrating differential expression, co-expression and gene network analysis for the identification of common genes associated with tumor angiogenesis deregulation

  2023cites this paper
• Cholesterol homeostasis, mechanisms of molecular pathways, and cardiac health: a current outlook.

  2023cites this paper
• Caveolin-1 and lipids: Association and their dualism in oncogenic regulation.

  2023cites this paper
• Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress

  2023influential citation
• Anti-hypercholesterolemic activity of standardized fermented Allium cepa L. var aggregatum extract: In vitro and in vivo studies

  2022cites this paper
• Peptides against Low Density Lipoprotein (LDL) Aggregation Inhibit Intracellular Cholesteryl Ester Loading and Proliferation of Pancreatic Tumor Cells

  2022cites this paper
• Tumor endothelial cell‐induced CD8+ T‐cell exhaustion via GPNMB in hepatocellular carcinoma

  2022cites this paper
• Radiotherapy-induced metabolic hallmarks in the tumor microenvironment.

  2022cites this paper
• Ezetimibe and Cancer: Is There a Connection?

  2022cites this paper
• Cholesterol homeostasis and cancer: a new perspective on the low-density lipoprotein receptor

  2022cites this paper
• Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential

  2022cites this paper
• A multi-marker integrative analysis reveals benefits and risks of bariatric surgery

  2022cites this paper
• GPR183 Regulates 7α,25-Dihydroxycholesterol-Induced Oxiapoptophagy in L929 Mouse Fibroblast Cell

  2022cites this paper
• Statins as adjuvants in the treatment of ovarian cancer: controversy and misunderstanding.

  2021cites this paper
• Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

  2021cites this paper
• Impact of Oxysterols on Cell Death, Proliferation, and Differentiation Induction: Current Status

  2021cites this paper
• Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

  2021cites this paper
• CD63+ and MHC Class I+ Subsets of Extracellular Vesicles Produced by Wild-Type and CD47-Deficient Jurkat T Cells Have Divergent Functional Effects on Endothelial Cell Gene Expression

  2021cites this paper
• Anti-tumor effect of statin on pancreatic adenocarcinoma: From concept to precision medicine

  2021cites this paper
• Cholesterol metabolism in prostate cancer

  2021cites this paper
• Role of cholesterol metabolism in the anticancer pharmacology of selective estrogen receptor modulators.

  2020cites this paper
• VEGF/VEGFR-2 system exerts neuroprotection against Phoneutria nigriventer spider envenomation through PI3K-AKT-dependent pathway.

  2020cites this paper
• Statin Drug Therapy May Increase COVID-19 Infection

  2020cites this paper
• Design and Synthesis of Tetrazole- and Pyridine-Containing Itraconazole Analogs as Potent Angiogenesis Inhibitors.

  2020cites this paper
• Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer

  2020cites this paper
• Systematic identification of drug-based prognostic biomarkersby integrating multiomics  in breast cancer

  2020cites this paper
• GDF15-Mediated Cholesterol Metabolism Promotes EMT and Metastasis in Esophageal Cancer

  2020cites this paper
• Roles of Farnesyl-Diphosphate Farnesyltransferase 1 in Tumour and Tumour Microenvironments

  2020cites this paper
• Ca2+-activated Cl− channel TMEM16A inhibition by cholesterol promotes angiogenesis in endothelial cells

  2020cites this paper
• Development of Autophagy Signature-Based Prognostic Nomogram for Refined Glioma Survival Prognostication

  2020cites this paper
• Cholesterol metabolism: New functions and therapeutic approaches in cancer.

  2020cites this paper
• Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway

  2019cites this paper
• Targeting cellular cholesterol for anticancer therapy

  2019cites this paper
• Protective Effects of Licochalcone A Ameliorates Obesity and Non-Alcoholic Fatty Liver Disease Via Promotion of the Sirt-1/AMPK Pathway in Mice Fed a High-Fat Diet

  2019cites this paper