title: L-5F, an apolipoprotein A-I mimetic, inhibits tumor angiogenesis by suppressing VEGF/basic FGF signaling pathways.
abstract: We recently reported that apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor growth and improve survival in a mouse model of ovarian cancer. The current study was designed to examine whether inhibition of angiogenesis is one of the mechanisms for the observed anti-tumorigenic effects. The apoA-I mimetic peptide L-5F had no affect on proliferation and cell viability of human umbilical vascular endothelial cells (HUVECs) in the basal state; however, treatment with L-5F at 1, 3, and 10 μg ml(-1), dose-dependently inhibited both vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-induced proliferation, cell viability, migration, invasion and tube formation in HUVECs. L-5F inhibited VEGF- and bFGF-induced activation of their corresponding receptors, VEGFR2 and FGFR1, as well as downstream signaling pathways, including Akt and ERK1/2. MicroCT scanning and immunohistochemistry staining demonstrated that daily injection of L-5F (10 mg kg(-1)) decreased both the quantity and size of tumor vessels in mice. L-5F treated mice showed significantly reduced levels of VEGF in both tumor tissue and the circulation, which is consistent with in vitro data showing that L-5F inhibited production and secretion of VEGF from mouse and human ovarian cell lines in the absence and presence of exogenously added lysophosphatidic acid, a potent tumor promoter. In conclusion, our data that L-5F inhibits angiogenesis suggests that apoA-I mimetic peptides may serve as novel anti-angiogenesis agents for the treatment of angiogenesis-associated diseases, including cancer.
authors.affiliation: David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-5347, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Sergio X
authors.initials: SX
authors.lastname: Vasquez
authors.forename: Feng
authors.initials: F
authors.lastname: Su
authors.forename: Svetlana
authors.initials: S
authors.lastname: Roberts
authors.forename: Neha
authors.initials: N
authors.lastname: Shah
authors.forename: Victor
authors.initials: V
authors.lastname: Grijalva
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.forename: Arnab
authors.initials: A
authors.lastname: Chattopadhyay
authors.forename: Ekambaram
authors.initials: E
authors.lastname: Ganapathy
authors.forename: David
authors.initials: D
authors.lastname: Meriwether
authors.forename: Brad
authors.initials: B
authors.lastname: Johnston
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
authors.forename: Robin
authors.initials: R
authors.lastname: Farias-Eisner
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry*; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D016632:Apolipoprotein A-I; D036341:Intercellular Signaling Peptides and Proteins; C472885:L-4F peptide; D008246:Lysophospholipids; D010446:Peptide Fragments; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; C431648:peptide 5F; D016222:Fibroblast Growth Factor 2; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C032881:lysophosphatidic acid