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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-03-0720.
Submitted March 8, 2002
Accepted June 14, 2002
Bis-indols a novel class of molecules enhancing the cyto-differentiating properties of retinoids in myeloid leukemia cells
Claudio Pisano, Peter Kollar, Maurizio Gianni', 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*
Department of Oncology, Sigma-Tau Industrie Farmaceutiche Riunite SPA, Rome, Italy
Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche, Milan, Italy
Department of Oncology, Sigma-Tau Industrie Farmaceutiche Riunite SPA, Rome, Italy; Biology, University of Istanbul, Istanbul, Istanbul, Turkey
Division of Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy
* Corresponding author; email: egarattini{at}marionegri.it.
Enhancing the pharmacological 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 cyto-differentiating activity of ATRA and synthetic RARa agonist in APL and other myelod leukemia cell lines. These agents have a bis-indolic structure 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 cyto-differentiating activity of ATRA by ST1346 enhances the efficacy of the retinoid in vivo, as demonstrated in the APL model of the SCID mouse transplanted with 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 cAMP-dependent CREB transcriptional complexes and enhances the level of expression of STAT1, two putative molecular determinants of the differentiation process activated by ATRA in APL cells. More importantly, ST1346 relieves the down-regulation of 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 MAP kinase in the molecular mechanisms underlying the pharmacological activity of the bis-indol.
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