The antiangiogenic effects of polyisoprenylated cysteinyl amide inhibitors in HUVEC, chick embryo and zebrafish is dependent on the polyisoprenyl moiety.
Angiogenesis is essential for solid tumor growth, therapeutic resistance and metastasis, the latest accounting for 90% of cancer deaths. Although angiogenesis is essential for the malignant transformations in solid tumors and therefore is an attractive target, few drugs are available that block tumor angiogenesis. The focus has been to block signaling by receptor tyrosine kinases (RTKs), such as for vascular endothelial growth factor (VEGF), whose activation abrogate apoptosis and promote angiogenesis. The polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to modulate aberrant polyisoprenylated small G-proteins such as mutant Ras whose constitutive activation promotes RTKs signaling. Since polyisoprenylation is essential for protein-protein interactions and functions of G-proteins, we hypothesized that the PCAIs would disrupt the monomeric G-protein signaling thereby effectively inhibiting angiogenesis. In this study we determined the effects of PCAIs on human umbilical vein endothelial cells (HUVEC) tube formation, cell viability, cell migration and invasion as well as in vivo using the chick chorioallantoic membrane (CAM) and zebrafish models. At sub- to low micromolar concentrations, the PCAIs inhibit the native and VEGF-stimulated cell migration and invasion as well as tube formation and angiogenesis in CAM and zebrafish embryos. The concentrations that block the angiogenic processes were lower than those that induce cell death. Since angiogenesis is essential for tumor growth but otherwise limited to wound healing, feeding fat cells and uterine wall repair in adults, it is conceivable that these compounds can be developed into safer therapeutics for cancers and retinal neovascularization that leads to loss of vision.
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.|Department of Biological Sciences, College of Science and Technology, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.
Augustine T
AT
Nkembo
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.
Elizabeth
E
Ntantie
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.
Olufisayo O
OO
Salako
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.
Felix
F
Amissah
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.
Rosemary A
RA
Poku
Department of Biological Sciences, College of Science and Technology, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.
Lekan M
LM
Latinwo
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee, Tallahassee, Florida 32307, USA.
Nazarius S
NS
Lamango
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002070:Butadienes / Q000737:chemistry; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects* / Q000196:embryology; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects* / Q000196:embryology; D045782:Hemiterpenes / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010420:Pentanes / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D015027:Zebrafish
D000577:Amides; D020533:Angiogenesis Inhibitors; D002070:Butadienes; D045782:Hemiterpenes; D010420:Pentanes; D011108:Polymers; C005059:isoprene
HUVEC; PCAIs; angiogenesis; cell invasion; zebrafish