Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis

Biochim Biophys Acta. 2009 Feb;1793(2):273-80. doi: 10.1016/j.bbamcr.2008.09.010. Epub 2008 Oct 7.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Apoptosis Inducing Factor / metabolism*
  • Apoptosis* / drug effects
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Enzyme Activation / drug effects
  • Ethylenediamines / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Leupeptins / pharmacology
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Models, Biological
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Protein Transport / drug effects
  • Pyrrolidines / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Thiocarbamates / pharmacology
  • Tumor Suppressor Protein p53 / deficiency*
  • Tumor Suppressor Protein p53 / genetics
  • Zinc / metabolism*

Substances

  • Apoptosis Inducing Factor
  • Ethylenediamines
  • Leupeptins
  • Pyrrolidines
  • Reactive Oxygen Species
  • Thiocarbamates
  • Tumor Suppressor Protein p53
  • pyrrolidine dithiocarbamic acid
  • Caspases
  • Zinc
  • N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde