Tumor-induced angiogenesis is essential for invasive growth and hematogenous metastasis of adenoid cystic carcinoma (ACC), a highly aggressive neoplasm mostly occurring in salivary glands. Previous studies have indicated that strategies directed against angiogenesis will help develop new therapeutics for ACC. The Chinese folk medicine licorice has been used for years as a natural remedy for angiogenesis-related diseases. Here we examined the effects of isoliquiritigenin (ISL), a flavonoid isolated from licorice, on the growth and viability of ACC cells, and observed a concentration-dependent (0-20 μM) inhibition of cell growth without cell death at 24 h. In a further mimic co-culture study, ISL effectively suppressed the ability of ACC cells to induce in vitro proliferation, migration and tube formation of human endothelial hybridoma (EAhy926) cells as well as ex vivo and in vivo angiogenesis, whereas it exerted no effect on EAhy926 cells when added directly or in the presence of vascular endothelial growth factor (VEGF). The data also showed that the specific suppression of tumor-angiogenesis by ISL was due to down-regulation of mTOR pathway-dependent VEGF production by ACC cells, correlating with concurrent activation of c-Jun NH2-terminal kinase (JNK) and inhibition of extracellular signal-regulated kinase (ERK). Most Importantly, ISL also significantly decreased the microvessel density (MVD) within xenograft tumors, associating with the reduction of VEGF production and suppression of mTOR pathway co-regulated by JNK and ERK, as revealed by immunohistochemical studies and clustering analysis. Collectively, our results highlight that ISL is a novel inhibitor of tumor-angiogenesis that possesses great therapeutic potential for ACC.
- Received March 11, 2010.
- Revision received May 17, 2010.
- Accepted May 17, 2010.
- The American Society for Pharmacology and Experimental Therapeutics