Effects of the angiotensin-I converting enzyme inhibitor perindopril on tumor growth and angiogenesis in head and neck squamous cell carcinoma cells
Effects of the angiotensin-I converting enzyme inhibitor perindopril on tumor growth and angiogenesis in head and neck squamous cell carcinoma cells
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DOI：
10.1007/s00432-004-0582-7
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发表时间：
2004-10-01
影响因子：
3.6
通讯作者：
Komune, S
中科院分区：
文献类型：
--
作者：
Yasumatsu, R;Nakashima, T;Komune, S
目的：血管紧张素转换酶（ACE）抑制剂具有抗癌活性。特别地，ACE抑制剂培哚普利显著抑制肝细胞癌细胞中的肿瘤生长和血管生成，沿着VEGF水平的抑制。然而，VEGF水平抑制的机制仍不清楚，并且没有关于此主题与头颈部鳞状细胞癌（HNSCC）相关的先前报告。在一些先前的研究中，血管紧张素II，其由血管紧张素I通过ACE产生，直接刺激VEGF表达。研究方法：在本研究中，我们集中在血管紧张素II，并研究了培哚普利对VEGF表达，血管生成和HNSCC肿瘤发展的影响，在体外和体内研究。结果：在体外细胞增殖实验中，培哚普利处理组与对照组之间无显著差异。然而，与对照组相比，培哚普利治疗组显示VEGF mRNA表达显著降低，并抑制VEGF启动子的诱导活性。培哚普利拉治疗也显着抑制血管紧张素II的生产在体外。在体内研究中，培哚普利对肿瘤生长具有显著的抑制作用，并减少肿瘤周围的血管形成。结论：我们的研究结果表明，培哚普利对肿瘤细胞没有直接的细胞毒性，但有可能抑制肿瘤生长，由于抑制VEGF诱导的血管生成在体内。血管紧张素II可能在肿瘤发生中起重要作用，培哚普利的抗血管生成活性至少部分由血管紧张素II抑制介导。血管紧张素转换酶抑制剂培哚普利作为一种有用的抗肿瘤药物具有临床潜力。
Purpose: Recently, it has been reported that angiotensin-I converting enzyme (ACE) inhibitors have anticancer activity. In particular, the ACE inhibitor, perindopril, significantly inhibits tumor growth and angiogenesis in hepatocellular carcinoma cells along with suppression of the VEGF level. However, the mechanisms of suppression of the VEGF level are still unclear, and there are no previous reports on this subject related to head and neck squamous cell carcinoma (HNSCC). In some previous studies, angiotensin II, which is produced from angiotensin I by ACE, directly stimulates VEGF expression. Methods: In the present study, we focused upon angiotensin II, and investigated the effect of perindopril on VEGF expression, angiogenesis, and tumor development of HNSCC with in vitro and in vivo studies. Results: In the in vitro cell proliferation assays, there was no significant difference between the perindopril-treated group and the control group. However, the perindoprilat-treated group showed a significant reduction in mRNA expression of VEGF and inhibited the induction activity of the VEGF promoter in comparison to the control group. Perindoprilat treatment also significantly suppressed angiotensin II production in vitro. In the in vivo studies, perindopril had a significant inhibitory effect on tumor growth, and reduced blood vessel formation surrounding the tumors. Conclusions: Our findings suggest that perindopril has no direct cytotoxicity against tumor cells, but has a potential to inhibit tumor growth due to suppression of VEGF-induced angiogenesis in vivo. Angiotensin II might have an important role in carcinogenesis, and the antiangiogenic activity of perindopril is at least partly mediated by angiotensin II inhibition. The ACE inhibitor perindopril has clinical potential as a useful antitumor agent.