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Role of nitric oxide in the anti-tumoral effect of retinoic acid and
1,25-dihydroxyvitamin D3 on human promonocytic leukemic cells
N Dugas, MD Mossalayi, A Calenda, A Leotard, P Becherel, F Mentz, F Ouaaz, M Arock, P Debre, J Dornand and B Dugas
Laboratorie Virus Neurone et Immunite IFR du Kremlin Bicetre, Kremlin
Bicetre, Montpellier, France.
All trans retinoic acid and vitamin D3 derivatives are well known for their
antileukemic activity, while the precise mechanism of this effect remains
to be clarified. Using human leukemic U937 and THP-1 promonocytic cell
lines, we analyzed the effect of all-trans retinoic acid (RA) and/or
1,25-dihydroxyvitamin D3 (VD) on the generation of nitric oxide (NO), a
potent antitumoral mediator. U937 cell differentiation with VD or with both
RA and VD (RA/VD) correlated with gene transcription and functional
expression of inducible nitric oxide synthase (iNOS). Nitrites and
L-citrulline were also detected in U937 cell supernatants as soon as 24
hours following cell incubation with VD or RA/VD, but not in cells treated
with RA alone. Inhibition of iNOS activity by NG-monomethyl-L-arginine
(LNMMA) significantly decreased in vitro U937 cell differentiation with VD
and RA/VD as shown by the expression of cell differentiation markers (CD14
and CD68) and by the capacity of these cells to undergo a luminol-dependent
chemiluminescence in response to opsonized zymosan. Similar results were
obtained using the THP-1 cell line strengthening the role of NO in the VD-
and RA/VD-induced growth arrest and terminal differentiation of
promonocytic leukemia cells.
Volume 88,
Issue 9,
pp. 3528-3534,
11/01/1996
Copyright © 1996 by The American Society of Hematology
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