Role of iron in tumor cell protection from the pro-apoptotic effect of nitric oxide.
F2The host defense against tumor cells is in part based upon the production of nitric oxide (NO) by activated macrophages. However, carcinogenesis may involve mechanisms that protect tumor cells from NO-mediated apoptosis. In the present study, we have assessed the effects of exogenous NO on the proliferation and survival of human liver (AKN-1), lung (A549), skin (HaCat), and pancreatic (Capan-2) tumor cell lines, compared with normal skin-derived epithelial cell cultures. Except to the HaCat cell line, all of the other human epithelioid cells were sensitive to the antiproliferation effect of S-nitroso-N-acetyl-penicillamine or Deta NONOate, whereas tumor cells had low if any response to sodium nitroprusside. Growth inhibition with exogenous NO correlated with increased apoptosis, but was not mediated by cyclic GMP, peroxynitrite generation, or poly(ADP-ribose) polymerase modulation, all of which involved in NO-mediated growth inhibition of normal skin-derived epithelial cell cultures. The simultaneous addition of iron-containing compounds protected tumor cells from NO-mediated growth inhibition and apoptosis. Intracellular iron quantification indicated that, as deferoxamine, exogenous NO significantly decreased intracellular ferric iron levels in tumor cells. Together, the current study reveals that intracellular iron elevation rescues tumor cells from NO-mediated iron depletion and subsequent growth inhibition and apoptosis.
Feger
F
F
Hematology Laboratory, Paris V Faculty of Pharmacy, 75006 Paris, France.
Ferry-Dumazet
H
H
Mamani Matsuda
M
M
Bordenave
J
J
Dupouy
M
M
Nussler
A K
AK
Arock
M
M
Devevey
L
L
Nafziger
J
J
Guillosson
J J
JJ
Reiffers
J
J
Mossalayi
M D
MD
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D005292:Ferricyanides / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D005292:Ferricyanides; D020030:Nitric Oxide Donors; C007931:hexacyanoferrate III; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D007501:Iron; D010396:Penicillamine