Coenzyme Q10 and alpha-tocopherol protect against amitriptyline toxicity

Oxidative Therapy Against Cancer

“…Chlorimipramine exerts its effect via the inhibition of complex III of the MRC (Daley et al, 2005). The same is valid for amitriptyline, as we have already reported (Cordero et al, 2009). We showed in fibroblasts treated with amitriptyline a decrease of expression level of proteins of complex I, complex III, cytochrome c, and reduced CoQ 10 levels.…”

“…So, amitriptyline-induced toxicity is caused through mitochondrial dysfunction, and increased mitochondrial ROS production. Moreover, CoQ level was decreased by amitriptyline treatment and CoQ and alpha-tocopherol supplementation ameliorated amitriptylineinduced toxicity in both cultured human primary fibroblasts and zebrafish embryos (Cordero et al, 2009). …”

“…Additionally, amitriptyline provokes an increase of intracellular lipid peroxidation in mouse 3T3 fibroblasts (Viola et al, 2000) and some mouse tissues (Bautista-Ferrufino et al, 2011), and many of these toxic effects are prevented by antioxidants (Slamon and Pentreath, 2000). Recently, our group has shown that amitriptyline induced toxicity is caused through a mitochondrial dysfunction, and increased ROS level (Moreno-Fernandez et al, 2008;Cordero et al, 2009). Amitriptyline reduced significantly the number of cultured cells; enhanced the production of stimulated lipid peroxidation, inverting the lipid reduced/oxidized ratio; decreased catalase protein levels, cytochrome c, ΔΨm, and citrate synthase activity; revealing mitochondrial damage.…”

“…The activation of MPTcauses mitochondria to become permeable to all solutes up to a molecular mass of about 1500 Da (Forte and Bernardi, 2005). After MPT, mitochondria undergo a dramatic swelling driven by colloid osmotic forces, which culminates in the rupture of the outer membrane and release of proapoptotic mitochondrial intermembrane proteins into the cytosol, such as cytochrome c, apoptosis inducing factor, Smac/Diablo, and others (Cordero et al,2009). …”

“…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).…”