Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Differential Effects of Doxazosin on Renin-Angiotensin-System- Regulating Aminopeptidase Activities in Neuroblastoma and Glioma Tumoral Cells

Author(s): María Jesús Ramírez-Expósito* and José Manuel Martínez-Martos

Volume 18, Issue 1, 2019

Page: [29 - 36] Pages: 8

DOI: 10.2174/1871527317666181029111739

Price: $65

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Alpha-1-adrenergic receptor, Neuroblastoma, Glioma, Aspartyl aminopeptidase, Aminopeptidase A, Aminopeptidase N, Aminopeptidase B, Insulin regulated aminopeptidase.

« Previous Next »
Graphical Abstract

[1]
Bianco J, Bastiancich C, Jankovski A, des Rieux A, Preat V, Danhier F. On glioblastoma and the search for a cure: Where do we stand? Cell Mol Life Sci 2017; 74(13): 2451-66.
[2]
Gaelzer MM, Coelho BP, de Quadros AH, et al. Phosphatidylinositol 3-Kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity. PLoS One 2016; 11(4): e0154612.
[3]
Staudacher I, Jehle J, Staudacher K, et al. HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells. PLoS One 2014; 9(2): e88164.
[4]
de la Chica-Rodriguez S, Cortes-Denia P, Ramirez-Exposito MJ, Martinez-Martos JM. Effects of alpha1-adrenergic receptor blockade by doxazosin on renin-angiotensin system-regulating aminopeptidase and vasopressin-degrading activities in male and female rat thalamus. Horm Metab Res 2007; 39(11): 813-7.
[5]
de la Chica-Rodriguez S, Cortes-Denia P, Ramirez-Exposito MJ, et al. In vivo administration of doxazosin in rats highly decreases serum circulating levels of testosterone through a mechanism involving the testicular renin-angiotensin system. Int J Androl 2008; 31(3): 364-70.
[6]
de la Chica-Rodriguez S, Cortes-Denia P, Ramirez-Exposito MJ, et al. Doxazosin blockade of alpha 1-adrenergic receptors increases rat serum progesterone levels: A putative role of ovarian angiotensin III in steroidogenesis. Fertil Steril 2007; 88(4)(Suppl.): 1071-5.
[7]
Saniger MA, Ramirez-Exposito MJ, de la Chica S, Carrera-Gonzalez MP, Mayas MD, Manuel Martinez-Martos J. Alpha-1-adrenergic receptor blockade modifies insulin-regulated aminopeptidase (IRAP) activity in rat prostate and modulates oxytocin functions. Drug Metab Lett 2011; 5(3): 192-6.
[8]
Mayas MD, Ramirez-Exposito MJ, Carrera MP, Cobo M, Martinez-Martos JM. Renin-angiotensin system-regulating aminopeptidases in tumor growth of rat C6 gliomas implanted at the subcutaneous region. Anticancer Res 2012; 32(9): 3675-82.
[9]
Wright JW, Harding JW. The brain renin-angiotensin system: A diversity of functions and implications for CNS diseases. Pflugers Arch 2013; 465(1): 133-51.
[10]
Escobar E, Rodriguez-Reyna TS, Arrieta O, Sotelo J. Angiotensin II, cell proliferation and angiogenesis regulator: Biologic and therapeutic implications in cancer. Curr Vasc Pharmacol 2004; 2(4): 385-99.
[11]
Arrieta O, Pineda-Olvera B, Guevara-Salazar P, et al. Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis. Br J Cancer 2008; 99(1): 160-6.
[12]
Juillerat-Jeanneret L, Celerier J, Chapuis Bernasconi C, et al. Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma. Br J Cancer 2004; 90(5): 1059-68.
[13]
Juillerat-Jeanneret L, Lohm S, Hamou MF, Pinet F. Regulation of aminopeptidase A in human brain tumor vasculature: Evidence for a role of transforming growth factor-beta. Lab Invest 2000; 80(6): 973-80.
[14]
Genest J, Cantin M, Garcia R, et al. Extrarenal angiotensin-forming enzymes. Clin Exp Hypertens A 1983; 5(7-8): 1065-80.
[15]
Johnston CI. ACE inhibitors and the kidney. Nephron 1990; 55(Suppl. 1): 1-2.
[16]
Ramirez-Exposito MJ, Martinez JM, Prieto I, Alba F, Ramirez M. Comparative distribution of glutamyl and aspartyl aminopeptidase activities in mouse organs. Horm Metab Res 2000; 32(5): 161-3.
[17]
Kambayashi Y, Bardhan S, Takahashi K, et al. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem 1993; 268(33): 24543-6.
[18]
Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol Chem 1993; 268(33): 24539-42.
[19]
Stegbauer J, Coffman TM. New insights into angiotensin receptor actions: From blood pressure to aging. Curr Opin Nephrol Hypertens 2011; 20(1): 84-8.
[20]
Blair-West JR, Coghlan JP, Denton DA, Funder JW, Scoggins BA, Wright RD. The effect of the heptapeptide (2-8) and hexapeptide (3-8) fragments of angiotensin II on aldosterone secretion. J Clin Endocrinol Metab 1971; 32(4): 575-8.
[21]
Ramirez-Exposito MJ, Martinez-Martos JM. Anti-inflammatory and antitumor effects of hydroxytyrosol but not oleuropein on experimental glioma in vivo. A putative role for the renin-angiotensin system. Biomedicines 2018; 6.
[22]
Illan-Cabeza NA, Jimenez-Pulido SB, Ramirez-Exposito MJ, et al. Structural and theoretical studies on rhodium and iridium complexes with 5-nitrosopyrimidines. Effects on the proteolytic regulatory enzymes of the renin-angiotensin system in human tumoral brain cells. J Inorg Biochem 2015; 143: 20-33.
[23]
Illan-Cabeza NA, Garcia-Garcia AR, Martinez-Martos JM, Ramirez-Exposito MJ, Moreno-Carretero MN. Antiproliferative effects of palladium(ii) complexes of 5-nitrosopyrimidines and interactions with the proteolytic regulatory enzymes of the renin-angiotensin system in tumoral brain cells. J Inorg Biochem 2013; 126: 118-27.
[24]
Ramirez-Exposito MJ, Mayas-Torres MD, Carrera-Gonzalez MP, et al. Silver(I)/6-hydroxyiminolumazine compounds differently modify renin-angiotensin system-regulating aminopeptidases A and N in human neuroblastoma and glioma cells. J Inorg Biochem 2014; 138: 56-63.
[25]
Illan-Cabeza NA, Garcia-Garcia AR, Martinez-Martos JM, Ramirez-Exposito MJ, Pena-Ruiz T, Moreno-Carretero MN. A potential antitumor agent, (6-amino-1-methyl-5-nitrosouracilato-N3)-triphenylphosphine-gold(I): Structural studies and in vivo biological effects against experimental glioma. Eur J Med Chem 2013; 64: 260-72.
[26]
Ni L, Feng Y, Wan H, et al. Angiotensin-(1-7) inhibits the migration and invasion of A549 human lung adenocarcinoma cells through inactivation of the PI3K/Akt and MAPK signaling pathways. Oncol Rep 2012; 27(3): 783-90.
[27]
George AJ, Thomas WG, Hannan RD. The renin-angiotensin system and cancer: Old dog, new tricks. Nat Rev Cancer 2010; 10(11): 745-59.
[28]
Sim MK, Choo MH, Qiu XS. Degradation of angiotensin I to [des-Asp1]angiotensin I by a novel aminopeptidase in the rat hypothalamus. Biochem Pharmacol 1994; 48(5): 1043-6.
[29]
Fujimura H, Ino K, Nagasaka T, et al. Aminopeptidase A expression in cervical neoplasia and its relationship to neoplastic transformation and progression. Oncology 2000; 58(4): 342-52.
[30]
Teranishi J, Ishiguro H, Hoshino K, Noguchi K, Kubota Y, Uemura H. Evaluation of role of angiotensin III and aminopeptidases in prostate cancer cells. Prostate 2008; 68(15): 1666-73.
[31]
Xu J, Fan J, Wu F, et al. The ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Pleiotropic Roles in Cancer. Front Physiol 2017; 8: 276.
[32]
Liu B, Liu Y, Jiang Y. Podocalyxin promotes glioblastoma multiforme cell invasion and proliferation by inhibiting angiotensin-(1-7)/Mas signaling. Oncol Rep 2015; 33(5): 2583-91.
[33]
Barrett AJ, Rawlings ND, Woessner JF. Handbook of proteolytic enzymes. Elsevier Academic Press: Amsterdam; Boston, MA 2004.
[34]
Axen A, Lindeberg G, Demaegdt H, Vauquelin G, Karlen A, Hallberg M. Cyclic insulin-regulated aminopeptidase (IRAP)/AT4 receptor ligands. J Pept Sci 2006; 12(11): 705-13.
[35]
Yang H, Zeng XJ, Wang HX, et al. Angiotensin IV protects against angiotensin II-induced cardiac injury via AT4 receptor. Peptides 2011; 32(10): 2108-15.
[36]
Dixon J, Kaklamanis L, Turley H, et al. Expression of aminopeptidase-n (CD 13) in normal tissues and malignant neoplasms of epithelial and lymphoid origin. J Clin Pathol 1994; 47(1): 43-7.
[37]
Varona A, Blanco L, Lopez JI, et al. Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma. Am J Physiol Renal Physiol 2007; 292(2): F780-8.
[38]
Wang D, Huang HJ, Kazlauskas A, Cavenee WK. Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res 1999; 59(7): 1464-72.
[39]
Jensen RL. Growth factor-mediated angiogenesis in the malignant progression of glial tumors: A review. Surg Neurol 1998; 49(2): 189-95. discussion 96.
[40]
Schmidt NO, Westphal M, Hagel C, et al. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 1999; 84(1): 10-8.
[41]
El Sharkawi FZ, El Shemy HA, Khaled HM. Possible anticancer activity of rosuvastatine, doxazosin, repaglinide and oxcarbazepin. Asian Pac J Cancer Prev 2014; 15(1): 199-203.
[42]
Petty A, Myshkin E, Qin H, et al. A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. PLoS One 2012; 7(8): e42120.

Rights & Permissions Print Cite
Article Metrics
50
7
1
© 2024 Bentham Science Publishers | Privacy Policy