@article{3091356,
    title = "Independent actions on cyclin-dependent kinases and aryl hydrocarbon
receptor mediate the antiproliferative effects of indirubins",
    author = "Knockaert, M and Blondel, M and Bach, S and Leost, M and Elbi, C and and Hager, GL and Nagy, SR and Han, D and Denison, M and Ffrench, M and and Ryan, XZP and Magiatis, P and Polychronopoulos, P and Greengard, P and and Skaltsounis, L and Meijer, L",
    journal = "Oncogenesis",
    year = "2004",
    volume = "23",
    number = "25",
    pages = "4400-4412",
    publisher = "Nature Publishing Group",
    issn = "2157-9024",
    doi = "10.1038/sj.onc.1207535",
    keywords = "aryl hydrocarbon receptor; indirubin; cyclin-dependent kinase; glycogen
synthase kinase; GSK-3 beta; kinase inhibitor; cancer",
    abstract = "Indirubin, a bis-indole obtained from various natural sources, is
responsible for the reported antileukemia activity of a Chinese
Medicinal recipe, Danggui Longhui Wan. However, its molecular mechanism
of action is still not well understood. In addition to inhibition of
cyclin-dependent kinases and glycogen synthase kinase-3, indirubins have
been reported to activate the aryl hydrocarbon receptor (AhR), a
cotranscriptional factor. Here, we confirm the interaction of AhR and
indirubin using a series of indirubin derivatives and show that their
binding modes to AhR and to protein kinases are unrelated. As reported
for other AhR ligands, binding of indirubins to AhR leads to its nuclear
translocation. Furthermore, the apparent survival of AhR-/- and +/+
cells, as measured by the MTT assay, is equally sensitive to the
kinase-inhibiting indirubins. Thus, the cytotoxic effects of indirubins
are AhR-independent and more likely to be linked to protein kinase
inhibition. In contrast, a dramatic cytostatic effect, as measured by
actual cell counts and associated with a sharp G1 phase arrest, is
induced by 1-methyl-indirubins, a subfamily of AhR-active but
kinase-inactive indirubins. As shown for TCDD (dioxin), this effect
appears to be mediated through the AhR-dependent expression of
p27(KIP1). Altogether these results suggest that AhR activation, rather
than kinase inhibition, is responsible for the cytostatic effects of
some indirubins. In contrast, kinase inhibition, rather than AhR
activation, represents the main mechanism underlying the cytotoxic
properties of this class of promising antitumor molecules."
}