7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Ribas, Judit; Bettayeb, Karima; Ferandin, Yoan; Knockaert, Marie; Garrofé-Ochoa, Xènia; Totzke, Frank; Schächtele, Christoph; Mešter, Ján; Polychronopoulos, Panagiotis; Magiatis, Prokopios; Skaltsounis, AL; Boix, Jacint; Meijer, Laurent

doi:10.1038/sj.onc.1209648

Cited by 102 publications

(113 citation statements)

References 49 publications

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“…Thus, in our experiments the CDKs seems to be about four times less sensitive to indirubin-3 0 -monoxime than FGFR1. Recently, it was reported that indirubin-3 0 -monoxime is able to inhibit the FGFR1 tyrosine kinase in an in vitro kinase assay with an IC 50 value of 0.74 mM while the IC 50 value for EGFR kinase was 102 mM (Ribas et al, 2006). The IC 50 values for CDK2/CycA, CDK2/CycE and CDK1/CycB obtained in this in vitro kinase assay were 2.3, 2.2 and 20 mM respectively, that is, considerably higher than the IC 50 value for FGFR1.…”

Section: Discussionmentioning

confidence: 99%

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

et al. 2007

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Indirubin-3 0 -monoxime is a derivative of the bis-indole alkaloid indirubin, an active ingredient of a traditional Chinese medical preparation that exhibits anti-inflammatory and anti-leukemic activities. Indirubin-3 0 -monoxime is mainly recognized as an inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3. It inhibits proliferation of cultured cells, mainly through arresting the cells in the G1/S or G2/M phase of the cell cycle. Here, we report that indirubin-3 0 -monoxime is able to inhibit proliferation of NIH/3T3 cells by specifically inhibiting autophosphorylation of fibroblast growth factor receptor 1 (FGFR1), blocking in this way the receptormediated cell signaling. Indirubin-3 0 -monoxime inhibits the activity of FGFR1 at a concentration lower than that required for inhibition of phosphorylation of CDK2 and retinoblastoma protein and cell proliferation stimulated by fetal calf serum. The ability of indirubin-3 0 -monoxime to inhibit FGFR1 signaling was similar to that of the FGFR1 inhibitor SU5402. In addition, we found that indirubin-3 0 -monoxime activates long-term p38 mitogen-activated protein kinase activity, which stimulates extracellular signal-regulated kinase 1/2 in a way unrelated to the activity of FGFR1. Furthermore, we show that indirubin-3 0 -monoxime can inhibit proliferation of the myeloid leukemia cell line KG-1a through inhibition of the activity of the FGFR1 tyrosine kinase. The data presented here demonstrate previously unknown activities of indirubin-3 0 -monoxime that may have clinical implications.

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Section: Discussionmentioning

confidence: 99%

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

et al. 2007

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“…To activate the TOPFLASH reporter we first used the 6-bromoindirubin-3′-oxime (BIO), a specific inhibitor of GSK3β (Ribas et al, 2006, Sato et al, 2004. Inactivation of GSK3β results in the nuclear accumulation of β-catenin, which activates the transcription of target genes in collaboration with TCF.…”

Section: Sry Represses the Wnt Signaling Pathway In A Cell-specific Mmentioning

confidence: 99%

Human SRY inhibits β-catenin-mediated transcription

Bernard

Sim

Knower

et al. 2008

The International Journal of Biochemistry & Cell Biology

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In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/β-catenin signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/β-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed β-catenin-mediated TCFdependent gene activation in the presence of a specific GSK3β inhibitor or an activated β-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of β-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit β-catenin; surprisingly four SRY sex reversed mutants with defective DNA binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of β-catenin involves neither DNA binding nor transactivation functions of SRY. β-catenin and SRY interact in-vitro and SRY expression triggered β-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits β-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.

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“…For comparison, the corresponding IC50 values for CDK1/cyclin B, CDK5/p25 and GSK-3α/β inhibition are also shown [18,20,62]. 21 of the 38 inhibitors had IC50's ≤ 10 µM for PhK-holo inhibition with the best of these having IC50's ~ 0.2 Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…Its analogue, KT5720, is a more specific inhibitor of PhK (Ki = 18.4 nM) and interactions leading to its specificity we have previously studied [5]. Meanwhile, competitive inhibitors from the indirubin family acting on CDKs and GSK-3 have been quite extensively studied [17][18][19][20] but information on their activity towards PhK has been limited and has in part motivated the current study [5]. Indirubin (1a, Scheme 1) is a natural bis-indol molecule found in plants and mollusks [21].…”

Section: Introductionmentioning

confidence: 99%

“…It has demonstrated antileukemic properties, although the exact mechanism of this remains unclear [22]. Modifications of indirubin have lead to the discovery of other potential anticancer compounds [20,[22][23][24]. The indirubin family of compounds target several kinases, some of which have been co-crystallised with indirubin analogues: GSK3, CDK2, CDK5, PfPK5 [18,[25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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An evaluation of indirubin analogues as phosphorylase kinase inhibitors

Begum

Skamnaki

Moffatt

et al. 2015

Journal of Molecular Graphics and Modelling

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Phosphorylase kinase (PhK) has been linked with a number of conditions such as glycogen storage diseases, psoriasis, type 2 diabetes and more recently, cancer (Camus S. et al., Oncogene 2012, 31, 4333). However, with few reported structural studies on PhK inhibitors, this hinders a structure based drug design approach. In this study, the inhibitory potential of 38 indirubin analogues have been investigated. 11 of these ligands had IC50 values in the range 0.170 -0.360 µM, with indirubin-3'-acetoxime (1c) the most potent. 7-bromoindirubin-3'-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas J. et al., Oncogene, 2006, 25, 6304) is revealed as a specific inhibitor of PhK (IC50 = 1.8 µM). Binding assay experiments performed using both PhK-holo and PhK-γtrnc confirmed the inhibitory effects to arise from binding at the kinase domain (γ subunit). High level computations using QM/MM-PBSA binding free energy calculations were in good agreement with experimental binding data, as determined using statistical analysis, and support binding at the ATP-binding site. The value of a QM description for the binding of halogenated ligands exhibiting σ-hole effects is highlighted. A new statistical metric, the 'sum of the modified logarithm of ranks' (SMLR), has been defined which measures performance of a model for both the "early recognition" (ranking earlier/higher) of active compounds and their relative ordering by potency. Through a detailed structure activity relationship analysis considering other kinases (CDK2, CDK5 and GSK-3α/β), 6'(Z) and 7(L) indirubin substitutions have been identified to achieve selective PhK inhibition. The key PhK binding site residues involved can also be targeted using other ligand scaffolds in future work.

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7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Cited by 102 publications

References 49 publications

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

Human SRY inhibits β-catenin-mediated transcription

An evaluation of indirubin analogues as phosphorylase kinase inhibitors

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