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Independent Actions on Cyclin-Dependent Kinases and Aryl Hydrocarbon Receptor Mediate the Antiproliferative Effects of Indirubins

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Independent Actions on Cyclin-Dependent Kinases and Aryl Hydrocarbon Receptor Mediate the Antiproliferative Effects of Indirubins Oncogene (2004) 23, 4400–4412 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins Marie Knockaert1, Marc Blondel1, Ste´ phane Bach1, Maryse Leost1, Cem Elbi2, Gordon L Hager2, Scott RNagy 3, Dalho Han3, Michael Denison3, Martine Ffrench4, Xiaozhou P Ryan5, Prokopios Magiatis6, Panos Polychronopoulos6, Paul Greengard5, Leandros Skaltsounis6 and Laurent Meijer*,1,5 1C.N.R.S., Cell Cycle Group & UPS-2682, Station Biologique, BP 74, 29682 ROSCOFF cedex, Bretagne, France; 2Laboratory of Receptor Biology & Gene Expression, Bldg 41, Room B602, National Cancer Institute, NIH, Bethesda, MD 20892-5055, USA; 3Department of Environmental Toxicology, Meyer Hall, One Shields Avenue, University of California, Davis, CA 95616-8588, USA; 4Universite´ Claude Bernard, Laboratoire de Cytologie Analytique et Cytoge´ne´tique Mole´culaire, 8 Avenue Rockefeller, 69373 Lyon Cedex 08, France; 5Laboratory of Molecular & Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA; 6Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece Indirubin, a bis-indole obtained from various natural Introduction sources, is responsible for the reported antileukemia activity of a Chinese Medicinal recipe, Danggui Longhui The bis-indole indirubin has been identified as the main Wan. However, its molecular mechanism of action is still active ingredient of a traditional Chinese medicinal not well understood. In addition to inhibition of cyclin- recipe, Danggui Longhui Wan, used to treat various dependent kinases and glycogen synthase kinase-3, diseases including chronic myelocytic leukemia (reviews indirubins have been reported to activate the aryl in Tang and Eisenbrand, 1992; Xiao et al., 2002). hydrocarbon receptor (AhR), a cotranscriptional factor. Indirubin can be obtained from four different natural Here, we confirm the interaction of AhR and indirubin sources: (1) a variety of indigo-producing plants using a series of indirubin derivatives and showthat their (Balfour-Paul, 1998; Maugard et al., 2001), (2) a number binding modes to AhR and to protein kinases are of mollusks, essentially belonging to the Muricidae unrelated. As reported for other AhR ligands, binding of family (reviewed in Cooksey, 2001), (3) urine of healthy indirubins to AhR leads to its nuclear translocation. and diseased patients (Dealler et al., 1988; Adachi et al., Furthermore, the apparent survival of AhRÀ/À and 2001 and references therein), and (4) various natural or þ / þ cells, as measured by the MTT assay, is equally recombinant bacteria (reviewed in Chotani et al., 2000; sensitive to the kinase-inhibiting indirubins. Thus, the Gillam et al., 2000; MacNeil et al., 2001). Indirubin is a cytotoxic effects of indirubins are AhR-independent and dark red isomer of the blue indigo. Both derive from the more likely to be linked to protein kinase inhibition. In spontaneous, nonenzymatic dimerization of isatin and contrast, a dramatic cytostatic effect, as measured by indoxyl, two colorless precursors found either free or actual cell counts and associated with a sharp G1 phase conjugated to carbohydrates. Interest in this family of arrest, is induced by 1-methyl-indirubins, a subfamily of compounds increased when indirubin and analogues AhR-active but kinase-inactive indirubins. As shown for (collectively referred to as indirubins) were found to TCDD (dioxin), this effect appears to be mediated inhibit the cell cycle regulating cyclin-dependent kinases through the AhR-dependent expression of p27KIP1. Alto- (CDKs) (Hoessel et al., 1999), and glycogen synthase gether these results suggest that AhR activation, rather kinase -3 (GSK-3) (Leclerc et al., 2001). Evidence than kinase inhibition, is responsible for the cytostatic suggests that the antiproliferative effects of indirubins effects of some indirubins. In contrast, kinase inhibition, derive from their ability to inhibit CDKs (Damiens et al., rather than AhR activation, represents the main mechan- 2001; Marko et al., 2001). However, the exact mechan- ism underlying the cytotoxic properties of this class of isms underlying the antimitotic and antitumor proper- promising antitumor molecules. ties of indirubins remain to be identified. Oncogene (2004) 23, 4400–4412. doi:10.1038/sj.onc.1207535 Indirubin and indigo have recently been discovered as Published online 12 April 2004 potent ligands of the aryl hydrocarbon receptor (AhR), also known as the dioxin receptor (Adachi et al., 2001; Keywords: aryl hydrocarbon receptor; indirubin; cyclin- Kawanishi et al., 2003). AhR, a member of the bHLH/ dependent kinase; glycogen synthase kinase; GSK-3b; PAS family of transcriptional regulators, mediates the kinase inhibitor; cancer effects of many xenobiotics such as 2,3,7,8-tetrachlor- odibenzo-p-dioxin (TCDD) and indole-containing com- pounds (reviewed in Hankinson, 1995; Denison and *Correspondence: L Meijer; E-mail: [email protected] Nagy, 2003). However, despite the large number of Received 5 August 2003; revised 10 November 2003; accepted 16 January compounds found to interact with AhR, its natural 2004; Published online 12 April 2004 ligands remain to be identified (Denison and Nagy, Indirubins, kinases and aryl hydrocarbon receptor M Knockaert et al 4401 2003). The binding of AhRto a ligand leads to its scription. Using the same yeast reporter assay, we tested translocation from the cytoplasm to the nucleus, a series of indirubin analogues for their ability to followed by complex formation with the aryl hydro- activate AhR-dependent transcription (Table 1). Addi- carbon receptor nuclear translocator (ARNT). This tionally, we also tested these compounds in a newly complex then binds to xenobiotic-responsive element described AhRagonist detection bioassay. In this assay, (XRE) and stimulates the transcription of a wide variety ligand and AhR-dependent transcription is measured by of genes, including cytochrome P450 Cyp1A1, p27kip1, the amount of enhanced green fluorescent protein myristoyltransferase, etc. (Rowlands and Gustafsson, (EGFP) expression which is stably transfected into a 1997; Denison et al., 1998; Kolluri et al., 1999, 2001; mouse hepatoma cell line (Nagy et al., 2002a, b) Santini et al., 2001). Several arguments support a link (Table 1, Figure 1). TCDD was used as a positive between AhRactivation and cell cycle control (Ge and control. Our results confirmed that indirubins, including Elferink, 1998; Elferink et al., 2001; reviewed in indirubin-30-oxime (IO), the analogue commonly used in Elferink, 2003). The recent discovery of the interaction cell cycle studies (Damiens et al., 2001; Marko et al., of indirubin with AhRopened the possibility that 2001), are potent AhRagonists, although much less indirubins prevent cell proliferation via an action than TCDD in the mammalian reporter assay (Table 1, through AhR. This could raise some concern about Figure 1). the potential use of these compounds since AhR We also tested the effect of indirubin analogues on activation has been directly linked to carcinogenesis two protein kinases, CDK1/cyclin B and GSK-3 (Hankinson, 1995; Shimizu et al., 2000; Safe, 2001; (Table 1). Interestingly, the indirubin structure/activity Andersson et al., 2002). In contrast, some AhRagonists relationships with respect to AhRbinding and kinase have also been reported to cause growth inhibition of inhibition were only distantly comparable (Table 1) (see various tumor cell lines and as such could be evaluated Discussion). for their use in antitumor therapy (Bradshaw et al., As revealed by cocrystal structures (Hoessel et al., 2002; Koliopanos et al., 2002; Safe and McDougal, 1999; Davies et al., 2001; Meijer et al., 2003) the 2002). indirubin N1 acts as a H-bond donor in the indirubin/ In this article, we report the results of experiments kinase binding. Consequently, methylation at this designed to investigate the contribution of indirubin/ site should clearly eliminate an essential bonding AhRinteraction to the antiproliferative properties of and inactivate indirubins as kinase inhibitors indirubins. We first confirm the interaction between (Meijer et al., 2003; Polychronopoulos et al., AhRand a series of indirubin analogues using two 2004). Based on this observation, we envisaged the distinct AhRreporter systems. We show that the synthesis of 1-methyl-indirubin, 1-methyl-indirubin-30- survival of AhR À/À and þ / þ cells, as measured by oxime (MeIO), 1-methyl-6-bromo-indirubin and 1- the MTT assay, is equally sensitive to the kinase- methyl-6-bromo-indirubin-30-oxime (MeBIO). Indeed, inhibiting indirubins and thus largely AhR-independent, these compounds were found to be the most striking therefore more likely linked to protein kinase inhibition. examples of selectivity, as they were very potent in the In contrast, the kinase-inactive, but AhR-active, 1- AhRassays while being essentially inactive on CDKs methyl-indirubins, show a striking AhR-dependent and GSK-3, compared to their nonmethylated counter- cytostatic effect leading to an arrest of cells in G1. This parts, indirubin (IO) and 6-bromo-indirubin-30-oxime effect appears to be directly linked to the AhR- (BIO), respectively. dependent expression of p27KIP1, as it is not observed These results show that indirubins are potent in AhR À/À cells. Altogether these
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