Reddy M K, Baskaran K, Molteni A
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611-3008, USA.
Proc Soc Exp Biol Med. 1995 Dec;210(3):221-6. doi: 10.3181/00379727-210-43942.
The angiotensin-converting enzyme (ACE) inhibitor captopril inhibits mitosis in several cell types that contain ACE and renin activity. In the present study, we evaluated the effect of the ACE inhibitors captopril and CGS 13945 (10(-8) to 10(-2) M) on proliferation and gene expression in hamster pancreatic duct carcinoma cells in culture. These cells lack renin and ACE activity. Both ACE inhibitors produced a dose-dependent reduction in tumor cell proliferation within 24 hr. Captopril at a concentration of 0.36 mM and CGS 13945 at 150 microM decreased cellular growth rate to approximately half that of the control. Neither drug influenced the viability or the cell cycle distribution of the tumor cells. Slot blot analysis of mRNA for four genes, proliferation associated cell nuclear antigen (PCNA), K-ras, protein kinase C-beta (PKC-beta) and carbonic anhydrase II (CA II) was performed. Both ACE inhibitors increased K-ras expression by a factor of 2, and had no effect on CA II mRNA levels. Captopril also lowered PCNA by 40% and CGS 13945 lowered PKC-beta gene expression to 30% of the control level. The data demonstrate that ACE inhibitors exhibit antimitotic activity and differential gene modulation in hamster pancreatic duct carcinoma cells. The absence of renin and ACE activity in these cells suggests that the antimitotic action of captopril and CGS 13945 is independent of renin-angiotensin regulation. The growth inhibition may occur through downregulation of growth-related gene expression.
血管紧张素转换酶（ACE）抑制剂卡托普利可抑制多种具有ACE和肾素活性的细胞类型的有丝分裂。在本研究中，我们评估了ACE抑制剂卡托普利和CGS 13945（10⁻⁸至10⁻²M）对培养的仓鼠胰腺导管癌细胞增殖和基因表达的影响。这些细胞缺乏肾素和ACE活性。两种ACE抑制剂在24小时内均产生了剂量依赖性的肿瘤细胞增殖减少。浓度为0.36 mM的卡托普利和150 microM的CGS 13945将细胞生长速率降低至对照的约一半。两种药物均未影响肿瘤细胞的活力或细胞周期分布。对四个基因，即增殖相关细胞核抗原（PCNA）、K-ras、蛋白激酶C-β（PKC-β）和碳酸酐酶II（CA II）的mRNA进行了狭缝印迹分析。两种ACE抑制剂均使K-ras表达增加了2倍，且对CA II mRNA水平无影响。卡托普利还使PCNA降低了40%，CGS 13945使PKC-β基因表达降低至对照水平的30%。数据表明，ACE抑制剂在仓鼠胰腺导管癌细胞中表现出抗有丝分裂活性和差异基因调节作用。这些细胞中缺乏肾素和ACE活性表明，卡托普利和CGS 13945的抗有丝分裂作用独立于肾素-血管紧张素调节。生长抑制可能通过下调生长相关基因表达而发生。
