RRC ID 67328
Author Shinya T, Yokota T, Nakayama S, Oki S, Mutoh J, Takahashi S, Sato K.
Title Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice.
Journal J Pharmacol Exp Ther
Abstract Angiogenesis, the formation of new blood vessels from pre-existing vessels, is essential for the growth and metastasis of tumors. In this study, we found that l-carbocisteine, a widely used expectorant, potently inhibits angiogenesis in vitro and in vivo. An in vivo Matrigel plug assay revealed that l-carbocisteine (2.5 mg/kg i.p. twice daily) significantly inhibited vascular endothelial growth factor (VEGF)-induced angiogenesis. l-Carbocisteine also suppressed VEGF-stimulated proliferation, migration, and formation of capillary-like structures of human umbilical vein endothelial cells (HUVECs). We examined the signaling pathways affected in VEGF-stimulated HUVECs, and found that l-carbocisteine significantly inhibited VEGF-induced phosphorylation of phospholipase C (PLC) γ, protein kinase C (PKC) μ, and extracellular signal-related kinases (ERK) 1/2, which have been shown to be essential for angiogenesis. However, these inhibitory effects of l-carbocisteine were not observed in the HeLa human cervical cancer cell line. An in vivo study of Colon-26 tumor-bearing mice found that tumor volumes were significantly smaller in mice treated with l-carbocisteine (150 mg/kg administered orally twice daily) in comparison with vehicle-treated mice. However, l-carbocisteine had no direct effect on Colon-26 cell proliferation or ERK activation. Collectively, our results suggest that l-carbocisteine inhibits tumor angiogenesis by suppressing PLCγ/PKC/ERK signaling.
Volume 354(3)
Pages 269-78
Published 2015-9-1
DOI 10.1124/jpet.115.224816
PII jpet.115.224816
PMID 26126534
MeSH Angiogenesis Inhibitors / pharmacology* Animals Carbocysteine / pharmacology* Cell Line Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects* Expectorants / pharmacology HeLa Cells Human Umbilical Vein Endothelial Cells / drug effects Human Umbilical Vein Endothelial Cells / metabolism Humans MAP Kinase Signaling System / drug effects Mice Mice, Inbred BALB C Mice, Inbred C57BL Neovascularization, Pathologic / drug therapy* Neovascularization, Pathologic / metabolism Phospholipase C gamma / metabolism Phosphorylation / drug effects Protein Kinase C / metabolism Signal Transduction / drug effects Vascular Endothelial Growth Factor A / metabolism
IF 3.561
Human and Animal Cells Colon-26(RCB2657)