Abstract
We show that treatment with non-toxic doses of zinc in association to the ionophore compound pyrrolidine dithiocarbamate (PDTC) inhibits p53(-/-) pancreatic cancer cell growth much more efficiently than gemcitabine, the gold standard chemotherapeutic agent for pancreatic cancer. Both the metal chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine and the radical scavenger N-acetyl-l-cysteine are able to recover cell growth inhibition by Zn/PDTC, demonstrating that this effect depends on the increased levels of intracellular zinc and of reactive oxygen species (ROS). Zn/PDTC treatment induces a strong apoptotic cell death that is associated to ROS-dependent nuclear translocation of the mitochondrial factor AIF, but not to the regulation of apoptotic genes and caspase activation. Primary fibroblasts are more resistant than pancreatic cancer cells to Zn/PDTC treatment and exhibit a lower basal and Zn/PDTC-induced enhancement of intracellular zinc. We show that Zn/PDTC induces p53 proteasomal degradation and that the proteasome inhibitor MG132 further increases fibroblast growth inhibition by Zn/PDTC, suggesting that p53 degradation plays an important role in fibroblast resistance to Zn/PDTC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Apoptosis Inducing Factor / metabolism*
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Apoptosis* / drug effects
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Caspases / metabolism
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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Enzyme Activation / drug effects
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Ethylenediamines / pharmacology
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Humans
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Intracellular Space / drug effects
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Intracellular Space / metabolism
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Leupeptins / pharmacology
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Mitochondria / drug effects
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Mitochondria / enzymology
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Models, Biological
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology*
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Protein Transport / drug effects
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Pyrrolidines / pharmacology
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Reactive Oxygen Species / metabolism*
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Thiocarbamates / pharmacology
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Tumor Suppressor Protein p53 / deficiency*
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Tumor Suppressor Protein p53 / genetics
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Zinc / metabolism*
Substances
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Apoptosis Inducing Factor
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Ethylenediamines
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Leupeptins
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Pyrrolidines
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Reactive Oxygen Species
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Thiocarbamates
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Tumor Suppressor Protein p53
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pyrrolidine dithiocarbamic acid
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Caspases
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Zinc
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N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde