OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt-NF-κB and MAPK signaling pathways.
Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt-nuclear factor-kappa B (NF-κB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU-A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt-NF-κB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, was observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt-NF-κB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy.
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Hany A
HA
Omar
El-Shaimaa A
el-SA
Arafa
Samir A
SA
Salama
Hany H
HH
Arab
Chieh-Hsi
CH
Wu
Jing-Ru
JR
Weng
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D000432:Methanol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000502:physiology
C523234:(1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl)-methanol; D020533:Angiogenesis Inhibitors; D007211:Indoles; D016328:NF-kappa B; D051058:Oncogene Protein v-akt; D000432:Methanol
4′,6-diamidino-2-phenylindole; Akt–NF-κB; Angiogenesis; CAM; DAPI; DMSO; EGM-2; Endothelial Cell Growth Medium-2; HUVECs; MAPKs; MMP-2; MMPs; MTT; NF-κB; OSU-A9; PARP; RA; Retinoic acid; VEGF; [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide]; chorioallantoic membrane; dimethyl sulfoxide; human umbilical vein endothelial cells; matrix metalloproteinases; mitogen-activated protein kinases; nuclear factor-kappa B; poly (ADP-ribose) polymerase; vascular endothelial growth factor