Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases

Hoessel, Ralph; Leclerc, Sophie; Endicott, Jane; Nobel, Martin E. M.; Lawrie, Alison M.; Tunnah, Paul; Leost, Maryse; Damiens, Eve; Marie, Dominique; Marko, Doris; Niederberger, Ellen; Tang, Weici; Eisenbrand, Gerhard; Meijer, Laurent

doi:10.1038/9035

Cited by 744 publications

(663 citation statements)

References 17 publications

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“…The bis-indole alkaloid indirubin is an active ingredient of a traditional Chinese medical preparation that exhibits anti-inflammatory activity and antileukemic activity against myelocytic leukemia (Hoessel et al, 1999). Indirubin and particularly indirubin derivatives such as indirubin-3 0 -monoxime and indirubin-5-sulfonate, which have low toxicity, have been considered as anticancer agents (Hoessel et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Indirubin and particularly indirubin derivatives such as indirubin-3 0 -monoxime and indirubin-5-sulfonate, which have low toxicity, have been considered as anticancer agents (Hoessel et al, 1999). Indirubin and its derivatives have been described as selective inhibitors of cyclin-dependent kinases (CDKs) such as CDK1/ cyclin B, CDK2/cyclin A, CDK2/cyclin E and CDK5/ p25 (Hoessel et al, 1999;Davies et al, 2001;Marko et al, 2001;Jautelat et al, 2005). It has been reported that these compounds are able to inhibit the proliferation of a variety of cultured cell types by a block in the G1/S or the G2/M phase of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…600 metaphases were scored for RI, and 6000 metaphases were scored for the MI; RI replication index, MI mitotic index, M 1, M 2 and M 3 metaphases 1, 2 and 3, respectively, Na 2 S 2 O 4 Sodium dithionite, MMC mitomycin-C, AE antigenotoxic and anti cancerogenic in Traditional Chinese Medicine. Hoessel et al (1999) reported that indirubin exhibited no toxic effect on bone marrow even in long-term studies. Also synthetic indirubin was reported to be a good antitumour agent and had only minor toxicity in animal models (Hoessel et al 1999).…”

Section: Sister-chromatid Exchange (Sce) and Mitotic Indices (Mi) Resmentioning

confidence: 99%

“…Hoessel et al (1999) reported that indirubin exhibited no toxic effect on bone marrow even in long-term studies. Also synthetic indirubin was reported to be a good antitumour agent and had only minor toxicity in animal models (Hoessel et al 1999). Mutagenic effect of the natural chemicals and some Isatis sp.…”

Section: Sister-chromatid Exchange (Sce) and Mitotic Indices (Mi) Resmentioning

confidence: 99%

“…In natural Isatis plants, some indigo precursors and indirubin known as red isomer of indigo were also tested for their genotoxicity (Candido-Bacani et al 2011) and indirubin and its derivatives were reported to possess low toxicity (Zhen et al 2007). Various biological activities including antifebrile, anti-inflammatory, antiviral, antimicrobial, detoxifying purposes, restenosis and skin psoriasis (Hoessel et al 1999;Chiang et al 2013;Liau et al 2007) and antileukemic activity against myelocytic leukemia in Traditional Chinese Medicine (Hoessel et al 1999) have been reported for indirubin and its derivatives (Hoessel et al 1999). Studies with respect to the monitoring the possible toxic effects of plant species are of great concern for public and environmental health for desired sustainable life comfort.…”

Section: Introductionmentioning

confidence: 99%

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The role of natural indigo dye in alleviation of genotoxicity of sodium dithionite as a reducing agent

et al. 2016

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Indigo blue is a natural dye used for thousands of years by civilizations to dye fabric blue and it is naturally obtained from Isatis tinctoria. I. tinctoria is not only used for extraction of indigo blue color but also used medicinally in Traditional Chinese Medicine because of its active compounds. Sodium dithionite (Na 2 S 2 O 4 ) is used in dye bath for indigo blue extraction, but this reducing agent and its derivatives are major pollutants of textile industry and subsequently have hazardous influences on public health. Herein, the present study was designed to obtain the high yield of natural indigo dye but with low possible toxic effect. In this context, genotoxic effects of particular combinations of natural dye solutions obtained from Isatis tinctoria subsp. tomentolla with Na 2 S 2 O 4 as reducing agent were investigated. Dye solutions were obtained using two different pH levels (pH 9 and 11) and three different concentrations of Na 2 S 2 O 4 (2.5, 5 and 10 mg/ml). In addition to the dye solutions and reducing agent, aqueous extracts of I. tinctoria were assessed for their genotoxicity on human lymphocytes. For in vitro testing of genotoxicity, chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and mitotic indexes (MI) assays were used. Accordingly, Na 2 S 2 O 4 caused significant increases in CA and SCE as well decrease in MI but the genotoxic effects of sodium dithionite were reduced with natural indigo dye. As a result, aqueous extracts of Isatis leaves removed the toxic effects of sodium dithionite and showed anti-genotoxic effect. For the optimal and desired quality but with less toxic effects of natural dye, 2.5 mg/ml (for wool yarn) and 5 mg/ml (for cotton yarn) of Na 2 S 2 O 4 doses were found to be the best doses for reduction in the dye bath at Ph 9.

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Marine Compounds as a New Source for Glycogen Synthase Kinase 3 Inhibitors

Alonso

Martı́nez

2006

Glycogen Synthase Kinase 3 (GSK‐3) and Its Inhibitors

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Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases

Cited by 744 publications

References 17 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

The role of natural indigo dye in alleviation of genotoxicity of sodium dithionite as a reducing agent

Marine Compounds as a New Source for Glycogen Synthase Kinase 3 Inhibitors

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