Angiogenesis, the formation of new blood vessels from preexisting 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) g, protein kinase C (PKC) m, 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 PLCg/PKC/ERK signaling.

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