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 alpha 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.