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.