Effects of tetrathiomolybdate and penicillamine on brain hydroxyl radical and free copper levels: A microdialysis study in vivo

Zhang, Jiwei; Liu, Junxiu; Hou, Haiman; Chen, Dingbang; Li, Feng; Wu, Chao; Wei, Liting; Li, Xunhua

doi:10.1016/j.bbrc.2015.01.071

Cited by 22 publications

(11 citation statements)

References 25 publications

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“…TTM, previously known as an anti-cancer Cu chelator when used as a single agent [ 46 ] paradoxically also helped revert apoptosis-associated PARP cleavage mediated by DSF and SOD, implying that basal Cu sequestration by TTM from DSF diminishes the latter ROS-inducing ability (47), implying that Cu bound to TTM behaves very differently to Cu bound to DSF. A recent comparison of Cu chelators TTM and penicillamine, showed that only the latter increased available Cu and oxidative stress in mouse brain, while TTM administration did not lead to comparable results [ 48 ]. Together, these data suggest that the potentiation of sub-toxic DSF activity against human melanoma and breast carcinoma cells irrespective of their BRAF or p53 mutant status and EGFR2/HER2 over-expression, is not merely related to Cu sequestration or increased Cu uptake by Cu chelators or ionophores, but rather to the ability of low DSF levels to increase basal Cu-dependent generation of ROS through higher intracellular hydroxyl radicals (•OH) production [ 19 ], since it is attenuated by the Cu chelator TTM or by the anti-oxidant NAC (Summary, Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate

2015

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Highlightsexogenous SOD increases apoptosis by sub-toxic disulfiram without copper overloadH2O2 generation from glucose oxidase also potentiates disulfiram toxicityN-acetylcysteine suppresses antitumor potentiation of DSF by H2O2 generationsub-toxic tetrathiomolybdate inhibits potentiation of DSF by SODBackgroundCu/Zn superoxide dismutases (SODs) like the extracellular SOD3 and cytoplasmic SOD1 regulate cell proliferation by generating hydrogen peroxide (H2O2). This pro-oxidant inactivates essential cysteine residues in protein tyrosine phosphatases (PTP) helping receptor tyrosine kinase activation by growth factor signaling, and further promoting downstream MEK/ERK linked cell proliferation. Disulfiram (DSF), currently in clinical cancer trials is activated by copper chelation, being potentially capable of diminishing the copper dependent activation of MEK1/2 and SOD1/SOD3 and promoting reactive oxygen species (ROS) toxicity. However, copper (Cu) overload may occur when co-administered with DSF, resulting in toxicity and mutagenicity against normal tissue, through generation of the hydroxyl radical (•OH) by the Fenton reaction.PurposeTo investigate: a) whether sub-toxic DSF efficacy can be increased without Cu overload against human melanoma cells with unequal BRAF(V600E) mutant status and Her2-overexpressing SKBR3 breast cancer cells, by increasing H2O2from exogenous SOD; b) to compare the anti-tumor efficacy of DSF with that of another clinically used copper chelator, tetrathiomolybdate (TTM)Resultsa) without copper supplementation, exogenous SOD potentiated sub-toxic DSF toxicity antagonized by sub-toxic TTM or by the anti-oxidant N-acetylcysteine; b) exogenous glucose oxidase, another H2O2 generator resembled exogenous SOD in potentiating sub-toxic DSF.Conclusionspotentiation of sub-lethal DSF toxicity by extracellular H2O2 against the human tumor cell lines investigated, only requires basal Cu and increased ROS production, being unrelated to non-specific or TTM copper chelator sequestration.SignificanceThese findings emphasize the relevance of extracellular H2O2 as a novel mechanism to improve disulfiram anticancer effects minimizing copper toxicity.

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Section: Discussionmentioning

confidence: 99%

Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate

2015

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“…Cu-loaded rats have shown increased MDA and reduced GSH levels in the cerebral cortex and basal ganglia (Ozcelik and Uzun 2009). Zhang et al showed that both hydroxyl radical and free copper markedly increased in the striatum of toxic milk mice during penicillamine administration, but were not elevated when administered tetrathiomolybdate (Zhang et al 2015). There was intense staining of ATP7A and CTR1 in the choroid plexus on day 3 and 10, but these changes were rare in the blood-brain barrier, suggesting redistribution of Cu in the brain parenchyma.…”

Section: Discussionmentioning

confidence: 93%

Role of Oxidative Stress in the Worsening of Neurologic Wilson Disease Following Chelating Therapy

2015

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Patients with neurologic Wilson disease (NWD) may worsen on treatment, but there is no study evaluating the role of oxidative stress. We report the role of plasma glutathione (GSH), total antioxidant capacity (TAC) and malondialdehyde (MDA) in the worsening of NWD following treatment. Fifty-one treatment-naïve NWD patients were subjected to detailed clinical evaluation. The severity of NWD was noted, and dystonia was measured by Burke-Fahn-Marsden (BFM) score. Their hematological, serum chemistry, ultrasound abdomen and cranial MRI changes were noted. Plasma GSH, TAC and MDA, serum free copper (Cu) and 24-h urinary Cu were measured at admission and at 3 and 6 months after treatment. The patients were considered worsened if there was one or more grade deterioration in severity scale, >10 % deterioration in BFM score or appearance of new neurologic signs. The median age of the patients was 11 (5-37) years, and 12 were females. Following treatment, 25 patients improved, 12 worsened, and 14 had stationary course. The worsened group at 3 months had lower GSH (1.99 ± 0.17 vs. 2.30 ± 0.30 mg/dl; P = 0.004) and TAC (1.59 ± 0.12 vs. 1.82 ± 0.17 mmol Trolox equivalent/L; P = 0.001) and higher MDA (5.24 ± 0.22 vs. 4.34 ± 0.46 nmol/ml; P < 0.001) levels compared to the improved group. These changes were associated with increased serum free Cu (41.81 ± 3.31 vs. 35.62 ± 6.40 µg/dl; P = 0.02) and 24-h urinary Cu (206.42 ± 41.61 vs. 121.99 ± 23.72 µg/24 h; P < 0.001) in the worsened compared to the improved group. All the patients having worsening were on penicillamine. Worsening following chelating treatment in NWD may be due to oxidative stress which is induced by increased serum free Cu. These results may have future therapeutic implication and needs further study.

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“…Similarly, in neurologic Wilson disease, excessive Cu chelation may cause local Cu deficiency in such Cu-requiring neurons as the neurons of LC and shift the catecholamine levels and/or ratio. Catecholamine misbalance may explain the worsening neurologic symptoms and psychotic episodes commonly observed in Wilson disease patients on Cu chelation therapy (42).…”

Section: Atp7a and Atp7b Oppositely Regulate Export Of Neuronal Dbhmentioning

confidence: 99%

ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase

Schmidt

Ralle

Schaffer

et al. 2018

Journal of Biological Chemistry

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Edited by Ruma Banerjee The copper (Cu) transporters ATPase copper-transporting alpha (ATP7A) and ATPase copper-transporting beta (ATP7B) are essential for the normal function of the mammalian central nervous system. Inactivation of ATP7A or ATP7B causes the severe neurological disorders, Menkes disease and Wilson disease, respectively. In both diseases, Cu imbalance is associated with abnormal levels of the catecholamine-type neurotransmitters dopamine and norepinephrine. Dopamine is converted to norepinephrine by dopamine-␤-hydroxylase (DBH), which acquires its essential Cu cofactor from ATP7A. However, the role of ATP7B in catecholamine homeostasis is unclear. Here, using immunostaining of mouse brain sections and cultured cells, we show that DBH-containing neurons express both ATP7A and ATP7B. The two transporters are located in distinct cellular compartments and oppositely regulate the export of soluble DBH from cultured neuronal cells under resting conditions. Down-regulation of ATP7A, overexpression of ATP7B, and pharmacological Cu depletion increased DBH retention in cells. In contrast, ATP7B inactivation elevated extracellular DBH. Proteolytic processing and the specific activity of exported DBH were not affected by changes in ATP7B levels. These results establish distinct regulatory roles for ATP7A and ATP7B in neuronal cells and explain, in part, the lack of functional compensation between these two transporters in human disorders of Cu imbalance. Copper (Cu) homeostasis is essential for the normal development and function of the mammalian brain (1-8). Either Cu deficiency or excess is highly detrimental. Two ATPdriven Cu transporters, ATP7A and ATP7B, play essential roles in balancing Cu levels in the brain. Inactivating mutations in either ATP7A or ATP7B are associated with severe neurologic disorders (Menkes disease and Wilson disease, respectively). In Menkes disease, one of the major biochemical hallmarks is an increased ratio of dopamine (DA) 2 to norepinephrine (NE), which is used as an early diagnostic marker of this disorder (9-12). In Wilson disease, catecholamine metabolism is also altered, as evidenced by a diminished secretion of DA and NE as well as an abnormal functioning of the dopaminergic system (13). Wilson disease patients present with parkinsonism, psychotic episodes, and schizophrenia, in addition to a spectrum of neurologic abnormalities. These clinical observations and similar findings in animal models of the Cu-related disorders suggest that both ATP7A and ATP7B contribute to catecholamine metabolism in the brain. However, our knowledge about specific roles of these transporters is very limited. Dopamine-␤-hydroxylase (DBH) is an important molecular link between the catecholamine metabolism and neuronal Cu homeostasis. This essential enzyme converts DA to NE in a reaction that requires a bound Cu cofactor (14, 15). DBH obtains Cu within the lumen of the secretory pathway during its biosynthetic maturation. Current evidence suggests that ATP7A, which transfers Cu from the cytoso...

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Effects of tetrathiomolybdate and penicillamine on brain hydroxyl radical and free copper levels: A microdialysis study in vivo

Cited by 22 publications

References 25 publications

Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate

Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate

Role of Oxidative Stress in the Worsening of Neurologic Wilson Disease Following Chelating Therapy

ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase

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