Abstract
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 α 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 CREBtranscriptional 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.
| Original language | English |
|---|---|
| Pages (from-to) | 3719-3730 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 100 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Nov 15 2002 |
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ASJC Scopus subject areas
- Hematology
Cite this
Bis-indols : A novel class of molecules enhancing the cytodifferentiating properties of retinoids in myeloid leukemia cells. / Pisano, Claudio; Kollar, Peter; Gianní, Maurizio; Kalac, Yesim; Giordano, Vincenzo; Ferrara, Fabiana Fosca; Tancredi, Richard; Devoto, Antonio; Rinaldi, Alessandra; Rambaldi, Alessandro; Penco, Sergio; Marzi, Mauro; Moretti, Giampiero; Vesci, Loredana; Tinti, Ornella; Carminati, Paolo; Terao, Mineko; Garattini, Enrico.
In: Blood, Vol. 100, No. 10, 15.11.2002, p. 3719-3730.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Bis-indols
T2 - A novel class of molecules enhancing the cytodifferentiating properties of retinoids in myeloid leukemia cells
AU - Pisano, Claudio
AU - Kollar, Peter
AU - Gianní, Maurizio
AU - Kalac, Yesim
AU - Giordano, Vincenzo
AU - Ferrara, Fabiana Fosca
AU - Tancredi, Richard
AU - Devoto, Antonio
AU - Rinaldi, Alessandra
AU - Rambaldi, Alessandro
AU - Penco, Sergio
AU - Marzi, Mauro
AU - Moretti, Giampiero
AU - Vesci, Loredana
AU - Tinti, Ornella
AU - Carminati, Paolo
AU - Terao, Mineko
AU - Garattini, Enrico
PY - 2002/11/15
Y1 - 2002/11/15
N2 - 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 α 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 CREBtranscriptional 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.
AB - 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 α 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 CREBtranscriptional 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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U2 - 10.1182/blood-2002-03-0720
DO - 10.1182/blood-2002-03-0720
M3 - Article
VL - 100
SP - 3719
EP - 3730
JO - Blood
JF - Blood
SN - 0006-4971
IS - 10
ER -