The State Key Laboratory Breeding Base of Basic Science of Stomatology, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
J Pharmacol Exp Ther. 2010 Aug;334(2):500-12. doi: 10.1124/jpet.110.167692. Epub 2010 May 18.
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 therapeutic agents for ACC. The Chinese folk medicine licorice has been used for years as a natural remedy for angiogenesis-related diseases. In this study, 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 microM) inhibition of cell growth without cell death at 24 h. In a further mimic coculture 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 caused by down-regulation of mammalian target of rapamycin (mTOR) pathway-dependent VEGF production by ACC cells, correlating with concurrent activation of c-Jun NH(2)-terminal kinase (JNK) and inhibition of extracellular signal-regulated kinase (ERK). Most importantly, ISL also significantly decreased microvessel density within xenograft tumors, associating with the reduction of VEGF production and suppression of the mTOR pathway coregulated by JNK and ERK, as revealed by immunohistochemical studies and clustering analysis. Taken together, our results highlight the fact that ISL is a novel inhibitor of tumor angiogenesis and possesses great therapeutic potential for ACC.
肿瘤诱导的血管生成对于腺样囊性癌（ACC）的侵袭性生长和血行转移至关重要，ACC 是一种主要发生在唾液腺的高度侵袭性肿瘤。先前的研究表明，针对血管生成的策略将有助于开发用于 ACC 的新治疗剂。中国民间医学甘草多年来一直被用作与血管生成相关疾病的天然疗法。在这项研究中，我们研究了异甘草素（ISL），一种从甘草中分离出的类黄酮，对 ACC 细胞生长和活力的影响，并观察到浓度依赖性（0-20 μM）抑制细胞生长，而在 24 小时内没有细胞死亡。在进一步的模拟共培养研究中，ISL 有效地抑制了 ACC 细胞诱导体外增殖、迁移和人内皮杂交瘤（EAhy926）细胞管形成的能力，以及体外和体内血管生成，而当直接添加或存在血管内皮生长因子（VEGF）时，ISL 对 EAhy926 细胞没有影响。数据还表明，ISL 对肿瘤血管生成的特异性抑制是由 ACC 细胞下调哺乳动物雷帕霉素靶蛋白（mTOR）通路依赖性 VEGF 产生引起的，与 c-Jun NH2-末端激酶（JNK）的同时激活和细胞外信号调节激酶（ERK）的抑制相关。最重要的是，ISL 还显著降低了异种移植肿瘤中的微血管密度，与 VEGF 产生减少和 JNK 和 ERK 共同调节的 mTOR 通路抑制相关，如免疫组织化学研究和聚类分析所示。总之，我们的研究结果强调了 ISL 是一种新型的肿瘤血管生成抑制剂，对 ACC 具有巨大的治疗潜力。
