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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2672-2682
Isolation and characterization of an acute promyelocytic leukemia
cell line selectively resistant to the novel antileukemic and
apoptogenic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene
carboxylic acid
Isabella Ponzanelli,
Maurizio Giannì,
Raffaella Giavazzi,
Angela Garofalo,
Ines Nicoletti,
Uwe Reichert,
Eugenio Erba,
Alessandro Rambaldi,
Mineko Terao, and
Enrico Garattini
From the Laboratory of Molecular Biology and the Department of
Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milano; the
Laboratory of Biology and Treatment of Metastasis, Laboratori Negri
Bergamo; the Division of Hematology, Ospedali Riuniti di Bergamo,
Bergamo, Italy; and Galderma Research and Development, Sophia
Antipolis, France.
6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid
(CD437) is a novel compound that represents the prototype of a new
class of synthetic retinoids with apoptogenic properties in acute
promyelocytic leukemia (APL) and other types of leukemia. In this
article, using SCID mice xenografted with APL-derived NB4 cells, we
demonstrate that CD437 has significant antileukemic activity in vivo.
In addition, we report on the isolation and characterization of an APL
cell line (NB4.437r) resistant to CD437. The cell line retains
expression of PML-RAR and is approximately 33-fold more resistant
than the parental counterpart to the apoptogenic effects of the
retinoid. Resistance is relatively specific to CD437 and structural
congeners because the NB4.437r cell line is still sensitive to various
types of apoptogenic compounds. The CD437-resistant cell line maintains
sensitivity to the antiproliferative and apoptotic action of
all-trans-retinoic acid, AM580, and fenretinide, though it shows
partial resistance to the cytodifferentiating effects of the first 2 compounds. Resistance to CD437 lays upstream of the CD437-induced
release of cytochrome c from the mitochondria and the activation of
caspase-3, -7, -8, and -9. Furthermore, NB4.437r cells are deficient in
the CD437-dependent activation of nuclear NFkb and AP1-binding
activities and in the phosphorylation of the protein kinase Akt. In the
case of AP1, deficient assembly of the complex is not caused by the
lack of activation of the Jun N-terminal kinase (JNK) family of
kinases. The novel cell line will be useful in the elucidation of the
molecular mechanisms underlying the apoptogenic action of CD437 and
structurally related retinoids.
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