TY - JOUR T1 - Orally Administered Mucolytic Drug <span class="sc">l</span>-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 269 LP - 278 DO - 10.1124/jpet.115.224816 VL - 354 IS - 3 AU - Tomohiro Shinya AU - Tsubasa Yokota AU - Shiori Nakayama AU - Sayuri Oki AU - Junpei Mutoh AU - Satoru Takahashi AU - Keizo Sato Y1 - 2015/09/01 UR - http://jpet.aspetjournals.org/content/354/3/269.abstract N2 - 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. ER -