Pyridoxal isonicotinoyl hydrazone analogs induce apoptosis in hematopoietic cells due to their iron-chelating properties.
Analogs of pyridoxal isonicotinoyl hydrazone (PIH) are of interest as iron chelators for the treatment of secondary iron overload and cancer. PIH, salicylaldehyde isonicotinoyl hydrazone (SIH), and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (NIH), the toxicity of which vary over two orders of magnitude, were selected for a study of their mechanisms of toxicity. PIH analogs and their iron complexes caused concentration- and time-dependent apoptosis in Jurkat T lymphocytes and K562 cells. Bcl-2 overexpression was partially anti-apoptotic, suggesting mitochondrial mediation of apoptosis. Since the pan-caspase inhibitor zVAD-fmk did not reduce lysosomal and mitochondrial destabilization, these events occur upstream of caspase activation. In contrast, phosphatidylserine externalization and the development of apoptotic morphology were inhibited significantly, indicating the role of caspases in mediating these later events. Since overexpression of CrmA had no effect on apoptosis, caspase-8 is not likely involved. Fe(3+) complexes of SIH and NIH, which accumulated in 59Fe-labeled mouse reticulocytes during incubation with the chelators, also caused apoptosis. BSA, which promotes release of the complexes from cells, reduced the toxicity of SIH and NIH, suggesting that the induction of apoptosis by PIH analogs involves toxic effects mediated by their Fe(3+) complexes. Moreover, analogs of these agents lacking the iron-chelating moiety were non-toxic.
Buss
Joan L
JL
Department of Physiology, McGill University, Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin de la Cote-Ste-Catherine, Montreal, Que., Canada H3T 1E2.
Neuzil
Jiri
J
Gellert
Nina
N
Weber
Christian
C
Ponka
Prem
P
D017209:Apoptosis; D005290:Ferric Compounds / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D020014:K562 Cells; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism
D005290:Ferric Compounds; D007502:Iron Chelating Agents; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D007501:Iron; D007538:Isoniazid