Orally administered mucolytic drug L-Carbocisteine inhibits angiogenesis and tumor growth in mices

Abstract

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.