Experimental and Clinical Physiopathology Research Group CTS1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaen, Jaen, Spain.
CNS Neurol Disord Drug Targets. 2019;18(1):29-36. doi: 10.2174/1871527317666181029111739.
It has been described that doxazosin, an antihypertensive drug, also promotes glioblastoma cells death by inhibiting cell proliferation, arresting cell cycle and inducing apoptosis. Doxazosin has also demonstrated several modulator effects on renin-angiotensin system (RAS)- regulating aminopeptidase activities, which are highly involved in tumor growth in experimental glioma. Therefore, it remains to elucidate if the anti-tumoral effects of doxazosin could also be mediated by the proteolytic regulatory components of the RAS.
To analyze the effects of doxazosin on cell growth and on RAS-regulating proteolytic regulatory aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase N (APN), aminopeptidase B (APB) and insulin-regulated aminopeptidase (IRAP) specific activities in the human neuroblastoma NB69 and astroglioma U373-MG tumoral cell lines.
Human neuroblastoma NB69 and astroglioma U373-MG cell lines were treated with doxazosin 50-500 μM for 24h or 48h. The effects on cell growth and on RAS-regulating aminopeptidase specific activities were analyzed.
Doxazosin treatments promote a concentration-dependent inhibition on cell growth in both NB69 and U373-MG cells, being NB69 cells more sensitive to the drug than U373-MG cells. However, its effects on RAS-regulating aminopeptidase specific activities depend on the concentration used, the duration of the treatment and the cell type. These data confirm the existence of a different dynamic progression of RAS cascade in each tumoral cell line as a consequence of the treatment with doxazosin and time of action, which also implies a very dynamic metabolism of the peptides which participate in each step of RAS cascade.
Our results indicate that doxazosin modifies the proteolytic regulatory enzymes of RAS cascade, modulating the bioactive efficacy of the different angiotensin peptides, and therefore, of their functional roles as initiators/promoters of cell proliferation as autocrine/paracrine mediators.
已有人描述道，降压药多沙唑嗪通过抑制细胞增殖、阻止细胞周期和诱导细胞凋亡，还能促进胶质母细胞瘤细胞死亡。多沙唑嗪还表现出对肾素-血管紧张素系统（RAS）调节氨肽酶活性的多种调节作用，这些作用在实验性神经胶质瘤中的肿瘤生长中起着至关重要的作用。因此，仍需要阐明多沙唑嗪的抗肿瘤作用是否也可以通过 RAS 的蛋白水解调节成分来介导。
分析多沙唑嗪对人神经母细胞瘤 NB69 和星形细胞瘤 U373-MG 肿瘤细胞系细胞生长和 RAS 调节蛋白水解调节天冬氨酰氨肽酶（ASAP）、氨肽酶 A（APA）、氨肽酶 N（APN）、氨肽酶 B（APB）和胰岛素调节氨肽酶（IRAP）特异性活性的影响。
用人神经母细胞瘤 NB69 和星形细胞瘤 U373-MG 细胞系用 50-500μM 的多沙唑嗪处理 24 小时或 48 小时。分析其对细胞生长和 RAS 调节氨肽酶特异性活性的影响。
多沙唑嗪处理可浓度依赖性地抑制 NB69 和 U373-MG 细胞的细胞生长，NB69 细胞比 U373-MG 细胞对药物更敏感。然而，其对 RAS 调节氨肽酶特异性活性的影响取决于所使用的浓度、处理时间和细胞类型。这些数据证实了由于多沙唑嗪的治疗和作用时间，每个肿瘤细胞系中 RAS 级联的存在不同的动态进展，这也意味着参与 RAS 级联的每一步的肽的代谢非常动态。
我们的结果表明，多沙唑嗪改变了 RAS 级联的蛋白水解调节酶，调节了不同血管紧张素肽的生物活性效力，因此，作为自分泌/旁分泌介质的细胞增殖的启动子/促进剂，它们的功能作用。
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