Abstract
The human pathology Wilson disease (WD) is characterized by toxic copper (Cu) accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs) that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp). The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS) and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.
Highlights
The human pathology Wilson disease (WD) is characterized by excess copper (Cu) accumulation in the brain and liver, leading to liver failure or cirrhosis and neurodegeneration [1,2,3]
We found that incubation of yeast cells with 2 mM Cu resulted in approx. 23% yeast survival, whereas treatment of Cu-stressed yeast with either 100 μM Candesartan Cilexetil, Losartan, Olmesartan Medoxomil or Valsartan significantly increased yeast survival
Exogenous addition of the plant decapeptide OSIP108 does not affect the protective effect of Candesartan Cilexetil against Cu-induced toxicity in yeast As we previously identified the A. thaliana-derived decapeptide OSIP108 [23] as a potent rescuer from Cu toxicity of yeast and human cells [18], we evaluated whether OSIP108 can influence the effect of Candesartan Cilexetil on Cu-induced cell death in yeast
Summary
The human pathology Wilson disease (WD) is characterized by excess copper (Cu) accumulation in the brain and liver, leading to liver failure or cirrhosis and neurodegeneration [1,2,3]. Cu toxicity is directly related to mitochondrial dysfunction and apoptosis in mammalian cells [4] as it induces oxidative stress [5, 6] and crosslinking of mitochondrial membrane proteins causing the membrane to contract [7]. Some reports have demonstrated the negative impact of non-lethal Cu doses on the mitochondrial proteome and function in yeast, resulting in decreased ATP production and activation of the oxidative stress response [15], and mitochondrial abnormalities [16]. We translated these data toward a novel zebrafish model for Cu toxicity and showed that OSIP108 injections into zebrafish larvae prevented Cu-induced hepatotoxicity and decreased oxidative stress levels [24]. Despite the contradictory reports in literature, by using our Cu-toxicity yeast screen, we identified OSIP108, and were able to translate our yeast data to higher eukaryotic cell models, as well as to an in vivo model for Cu-intoxication, thereby validating our Cu-
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