Deferasirox is a powerful NF-kappaB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging.
BACKGROUND
Usefulness of iron chelation therapy in myelodysplastic patients is still under debate but many authors suggest its possible role in improving survival of low-risk myelodysplastic patients. Several reports have described an unexpected effect of iron chelators, such as an improvement in hemoglobin levels, in patients affected by myelodysplastic syndromes. Furthermore, the novel chelator deferasirox induces a similar improvement more rapidly. Nuclear factor-kappaB is a key regulator of many cellular processes and its impaired activity has been described in different myeloid malignancies including myelodysplastic syndromes.


METHODS
We evaluated deferasirox activity on nuclear factor-kappaB in myelodysplastic syndromes as a possible mechanism involved in hemoglobin improvement during in vivo treatment. Forty peripheral blood samples collected from myelodysplastic syndrome patients were incubated with 50 muM deferasirox for 18h.


RESULTS
Nuclear factor-kappaB activity dramatically decreased in samples showing high basal activity as well as in cell lines, whereas no similar behavior was observed with other iron chelators despite a similar reduction in reactive oxygen species levels. Additionally, ferric hydroxyquinoline incubation did not decrease deferasirox activity in K562 cells suggesting the mechanism of action of the drug is independent from cell iron deprivation by chelation. Finally, incubation with both etoposide and deferasirox induced an increase in K562 apoptotic rate.


CONCLUSIONS
Nuclear factor-kappaB inhibition by deferasirox is not seen from other chelators and is iron and reactive oxygen species scavenging independent. This could explain the hemoglobin improvement after in vivo treatment, such that our hypothesis needs to be validated in further prospective studies.
Messa
Emanuela
E
Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Regione Gonzole 10, 10043 Orbassano, Torino, Italy.
Carturan
Sonia
S
Maffè
Chiara
C
Pautasso
Marisa
M
Bracco
Enrico
E
Roetto
Antonella
A
Messa
Francesca
F
Arruga
Francesca
F
Defilippi
Ilaria
I
Rosso
Valentina
V
Zanone
Chiara
C
Rotolo
Antonia
A
Greco
Elisabetta
E
Pellegrino
Rosa M
RM
Alberti
Daniele
D
Saglio
Giuseppe
G
Cilloni
Daniela
D
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D000077588:Deferasirox; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007501:Iron / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
D001565:Benzoates; D007502:Iron Chelating Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014230:Triazoles; D007501:Iron; D000077588:Deferasirox