Cytotoxic effects of amitriptyline in human fibroblasts

Fernández, Antonio J. Sánchez; Cordero, Mario D.; Miguel, Manuel de; Delgado-Rufino, M.D.; Sánchez-Alcázar, José Antonio; Navas, Plácido

doi:10.1016/j.tox.2007.09.021

Cited by 25 publications

(23 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, tumor cells frequently possess very little antioxidative enzymes, such as catalase, SOD, and glutathione peroxidase, which are known to play a protective role against ROS in normal cells. We have observed in normal fibroblast treated with amitriptyline a decrease in protein expression of antioxidant enzymes (catalase and MnSOD) 16 h after the treatment, followed by restored levels after 24h, as a mechanism of antioxidant defense (Moreno-Fernández et al, 2008). Interestingly, in cancer cells, the same concentration of amitriptyline provoked an unrestorable decrease of catalase (Cordero et al, 2010).…”

Section: Amitriptyline As An Anti-cancer Agentmentioning

confidence: 90%

“…Chlorimipramine, another tricyclic antidepressant, has been already proposed as a novel anticancer agent targeted to mitochondria as it induces caspase-3-dependent apoptosis (Daley et al, 2005). Several reports showed that the toxicity of this drug is due to an increase in oxidative stress by the generation of high amounts of ROS (Daley et al, 2005;Moreno-Fernández et al, 2008;Cordero et al, 2009). Therefore, amitriptyline has being proposed to be used for anticancer oxidant therapy against tumors that present significant oxidative stress and/or low antioxidant defences (Cordero et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oxidative Therapy Against Cancer

Miguel¹,

Cordero²

2012

Oxidative Stress and Diseases

View full text Add to dashboard Cite

Section: Amitriptyline As An Anti-cancer Agentmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Oxidative Therapy Against Cancer

Miguel¹,

Cordero²

2012

Oxidative Stress and Diseases

View full text Add to dashboard Cite

“…Interestingly, autophagy was initiated roughly 2 days before the onset of apoptosis and therefore is unlikely to account directly for activated caspase-3 and DNA fragmentation. Numerous studies describe apoptotic events arising from AD exposure, using either glioma cell lines, fibroblasts, or dorsal root ganglia neurons as cellular models (Levkovitz et al, 2005;Lirk et al, 2006;Moreno-Fernandez et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

Zschocke

Zimmermann

Berning

et al. 2011

Neuropsychopharmacol

View full text Add to dashboard Cite

In the search for antidepressants' (ADs') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI-and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis.

show abstract

“…Moreover, Tai et al (2009) observed that amitriptyline inhibits the expression of proinflammatory cytokines through increased IL-10, corroborating the concept that these TCAs may act as inflammatory suppressors (Xia et al 1996;Yaron et al 1999;Achar et al 2003;Tai et al 2009). However, studies exist reporting possible cytotoxic effects of amitriptyline (Viola et al 2000;Kitagawa et al 2006;Lirk et al 2006;Moreno-Fernandez et al 2008;Cordero et al 2009), manifested through lipid peroxidation, decreased levels of cytochrome C and other alterations that indicate mitochondrial injury, suggesting that amitriptyline induces oxidative stress, which is known to increase the intensity of the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“…Once Opn is mainly detected in the urothelium, the decrease in protein expression in obstructed rats could be associated with the lesion of this layer, caused by stretching or ischaemia and reperfusion, which occurs in bladder tissue owing to IVO. In the case of amitriptyline, besides the injury itself, the obstruction could also elicit the mitochondrial damage and increased oxidative stress that this drug causes among the fibroblasts and may be a factor in the diminished synthesis of Opn (Viola et al 2000;Kitagawa et al 2006;Lirk et al 2006;Moreno-Fernandez et al 2008;Cordero et al 2009). Another aspect that should be emphasized in relation to Opn and fibrosis, which strengthens our findings, is that this molecule appears to have a protective function in the process of tissue regeneration and survival of certain cell types, while its reduction shows deleterious effect on the process (Diamond et al 1995;Ophascharoensuk et al 1999;Denhardt et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Amitriptyline aggravates the fibrosis process in a rat model of infravesical obstruction

Prado

Soares

Lima

et al. 2012

Int J Experimental Path

View full text Add to dashboard Cite

Infravesical obstruction (IVO) secondary to benign prostatic hypertrophy can affect up to 50% of men over 50 years old and may cause serious and irreversible alterations throughout the urinary tract, especially in the bladder. Therapeutic approaches are currently limited. Amitriptyline has recently been described as an analgesic, anti-inflammatory and myorelaxant in some experimental models. The objective of this study was to investigate the effects of amitriptyline hydrochloride on the process of fibrosis in a bladder outlet obstruction model in rats. Male Wistar rats were subjected to IVO and studied at intervals of 1 and 14 days postprocedure. The rats were randomly divided into five groups: sham, IVO1-T, IVO1-NT, IVO14-T and IVO14-NT. Bladder tissue was processed for histopathology, immunohistochemistry and RT-PCR. The IVO14 groups presented bladder fibrosis, smooth muscle cell hypertrophy and bladder wall thickening. The IVO14-T group demonstrated a higher intensity of fibrosis, higher macrophage infiltration rate and higher gene expression of Transforming growth factor (TGF) Tgf-β1. Thus this data shows that in this experimental mode amitriptyline had an amplifying effect on the process of fibrosis as a whole.

show abstract

Cytotoxic effects of amitriptyline in human fibroblasts

Cited by 25 publications

References 22 publications

Oxidative Therapy Against Cancer

Oxidative Therapy Against Cancer

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

Amitriptyline aggravates the fibrosis process in a rat model of infravesical obstruction

Contact Info

Product

Resources

About