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

Abstract

Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Here we identify indirubin and its analogues as potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell cycle. These results have implications for therapeutic optimization of indigoids.

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

“…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).…”

“…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.…”

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

“…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).…”

“…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.…”

“…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.…”