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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-03-0720.
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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3719-3730
NEOPLASIA
Bis-indols: a novel class of molecules enhancing the
cytodifferentiating properties of retinoids in myeloid leukemia
cells
Claudio Pisano,
Peter Kollar,
Maurizio Gianní,
Yesim Kalac,
Vincenzo Giordano,
Fabiana Fosca Ferrara,
Richard Tancredi,
Antonio Devoto,
Alessandra Rinaldi,
Alessandro Rambaldi,
Sergio Penco,
Mauro Marzi,
Giampiero Moretti,
Loredana Vesci,
Ornella Tinti,
Paolo Carminati,
Mineko Terao, and
Enrico Garattini
From the Istituto di Ricerche Farmacologiche
"Mario Negri," Laboratory of Molecular Biology, Centro Catullo e
Daniela Borgomainerio, Milano, Italy; the University of Istanbul,
Faculty of Science, Department of Biology, Vezneciler, Istanbul,
Turkey; the Department of Oncology, Sigma-Tau Industrie Farmaceutiche
Riunite S.p.A., Pomezia, Italy; and the Division of Hematology,
Ospedali Riuniti di Bergamo, Largo Barozzi, Bergamo,
Italy.
Enhancing the pharmacologic activity of all-trans
retinoic acid (ATRA) is potentially useful in the management of acute
promyelocytic leukemia (APL) and other types of myeloid leukemia. In
this report, we identify a novel class of experimental agents
selectively potentiating the cytodifferentiating activity of ATRA
and synthetic retinoic acid receptor  agonists in APL and
other myeloid leukemia cell lines. These agents have a bis-indolic
structure (BISINDS), and ST1346 is the prototypical compound of the
series. Gene-profiling experiments and determination of the level of
expression of myeloid-associated markers indicate that ST1346
stimulates many aspects of the granulocytic maturation process set in
motion by ATRA. Stimulation of the cytodifferentiating activity of ATRA
by ST1346 enhances the efficacy of the retinoid in vivo, as
demonstrated in the APL model of the severe combined immunodeficiency
(SCID) mouse receiving transplants of NB4 cells. Although the
molecular mechanisms underlying the ATRA-potentiating action of ST1346
and congeners have not been completely clarified, bis-indols
are not ligands and do not exert any direct effect on the
ATRA-dependent transactivation of nuclear receptors. However, ST1346 inhibits the down-regulation of cyclic adenosine monophosphate (cAMP)-dependent CREB transcriptional complexes and
enhances the level of expression of signal transducers and activators
of transcription-1 (STAT1), 2 putative molecular determinants of the
differentiation process activated by ATRA in APL cells. More
importantly, ST1346 relieves the down-regulation of Jun N-terminal
kinases (JNK) afforded by ATRA. In addition, a specific JNK
inhibitor blocks the enhancing effect of ST1346 on ATRA-induced
maturation of NB4 cells. This demonstrates an important role for the
mitogen-activated protein kinase in the molecular mechanisms
underlying the pharmacologic activity of the bis-indol.
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