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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1045-1061
The Novel Synthetic Retinoid
6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437)
Causes Apoptosis in Acute Promyelocytic Leukemia Cells Through Rapid
Activation of Caspases
Luca Mologni,
Isabella Ponzanelli,
Filippo Bresciani,
Gabriele Sardiello,
Daniele Bergamaschi,
Maurizio Gianní,
Uwe Reichert,
Alessandro Rambaldi,
Mineko Terao, and
Enrico Garattini
From the Laboratory of Molecular Biology, Centro Catullo e Daniela
Borgomainerio, Laboratory of Cancer Chemotherapy, Istituto di Ricerche
Farmacologiche "Mario Negri," Milano, Italy; GALDERMA Research
and Development, Sophia Antipolis; and the Divisione di Ematologia,
Ospedali Riuniti di Bergamo, Bergamo, Italy.
The synthetic retinoid
6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid
(CD437), which was originally developed as an retinoic acid receptor
(RAR)- agonist, induces rapid apoptosis in all-trans retinoic acid
(ATRA)-sensitive and ATRA-resistant clones of the NB4 cell line, a
widely used experimental model of acute promyelocytic leukemia (APL).
In addition, the compound is apoptogenic in primary cultures of freshly
isolated APL blasts obtained from a newly diagnosed case and an
ATRA-resistant relapsed patient. NB4 cells in the S-phase of the cycle
are most sensitive to CD437-triggered apoptosis. CD437-dependent
apoptosis does not require de novo protein synthesis and activation of
RAR- or any of the other nuclear retinoic acid receptors. The
process is preceded by rapid activation of a caspase-like enzymatic
activity capable of cleaving the fluorogenic DEVD but not the
fluorogenic YVAD tetrapeptide. Increased caspase activity correlates
with caspase-3 and caspase-7 activation. Inhibition of caspases by
z-VAD suppresses the nuclear DNA degradation observed in NB4 cells
treated with CD437, as well as the degradation of pro-caspase-3 and
pro-caspase-7. CD437-dependent activation of caspases is preceded by
release of cytochrome c from the mitochondria into the cytosol of
treated cells. Leakage of cytochrome c lays upstream of caspase
activation, because the phenomenon is left unaffected by pretreatment
of NB4 cells with z-VAD. Treatment of APL cells with CD437 is
associated with a caspase-dependent degradation of
promyelocytic leukemia-RAR- , which can be completely
inhibited by z-VAD.
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