Disease relevance of Indirubin

• Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases [1].
• Here, we show that the indirubin derivatives E564, E728, and E804 potently block constitutive Stat3 signaling in human breast and prostate cancer cells [2].
• The bis-indole indirubin is an active ingredient of Danggui Longhui Wan, a traditional Chinese medicine recipe used in the treatment of chronic diseases such as leukemias [3].
• Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia [4].
• Characterization of a forest soil metagenome clone that confers indirubin and indigo production on Escherichia coli [5].

High impact information on Indirubin

• 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 [1].
• Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases [1].
• Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells [2].
• The antiapoptotic proteins Mcl-1 and Survivin, which are encoded in target genes of Stat3, were down-regulated by indirubin derivatives, followed by induction of apoptosis [2].
• This effect is mimicked by the structurally independent inhibitors of GSK-3, FRAT1, and indirubin [6].

Chemical compound and disease context of Indirubin

• The bis-indole indirubin is the active ingredient of the Traditional Chinese Medicine recipe Danggui Longhui Wan used against chronic myelocytic leukemia [7].
• Meisoindigo, a second generation derivative of indirubin, is an effective chemotherapeutic agent with very low toxicity used in the treatment of chronic myeloid leukemia [8].
• A wild-type naphthalene-degrading strain Pseudomonas putida RKJ1 and two recombinant strains each of Ps. putida and Escherichia coli carrying the genes for naphthalene degradation on a recombinant plasmid pRKJ3, produced indigo and indirubin pigments from indole [9].

Biological context of Indirubin

• Indirubin, the active component of a traditional Chinese herbal medicine, has been shown previously to inhibit cyclin-dependent kinases, resulting in cell cycle arrest [2].
• Further studies showed that indirubin blocked the phosphorylation and degradation of IkappaB alpha through the inhibition of activation of IkappaB alpha kinase and phosphorylation and nuclear translocation of p65 [10].
• Histologically, treatment with indirubin derivatives caused significant inhibition of tumor formation with increased apoptosis and decreased tumor cell proliferation [11].
• The gene expression profiles for TCDD and indirubin were very similar [12].
• Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site [13].

Anatomical context of Indirubin

• Inhibition of RANTES expression by indirubin in influenza virus-infected human bronchial epithelial cells [14].
• Indirubin was metabolized by microsomes containing cDNA-expressed human CYP1A1 or CYP1B1 [15].
• Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL-60 cells [16].
• The amount of interferon-gamma in the culture supernatants of elicited mouse lymphocytes was inhibited by indirubin treatment [17].
• Use of stable cloned HL-60 cells that contained a reporter vector for monitoring the activity of the transcription factor PU.1, which acts specifically at the stage of promyelocyte differentiation into neutrophils and monocytes, revealed that indirubin has a potent promoting activity on intracellular PU [16].

Associations of Indirubin with other chemical compounds

• Oxidation of indole by cytochrome P450 (P450) has been shown to generate species (indoxyl, isatin) that couple to yield indigo and indirubin [18].
• MALDI-MS analyses of liver and urine pigment both identified a product with a protonated molecular ion at m/z 977, suggesting formation of indirubin-like and indigo-like pigments [19].
• In this work, we describe an HPLC method dedicated to the identification and quantification of indigoid pigments (indigo, indirubin, isoindigo and isoindirubin) and indigo precursors produced in I. tinctoria (Woad) [20].
• In addition, it was found that enzymatic hydrolysis of calanthoside with beta-glucosidase furnished tryptanthrin together with a small amount of indirubin and isatin, whereas indirubin and isatin were obtained from calanthoside by acid hydrolysis [21].
• Variant TOM A113G was unable to form indigo, indirubin, or isoindigo (did not hydroxylate the indole pyrrole ring), but produced 4-hydroxyindole and unknown yellow compounds from C-4 hydroxylation of the indole benzene ring [22].

Gene context of Indirubin

• The potency of indirubin was comparable to that of TCDD in a CYP1B1-promoter-driven luciferase assay, when MCF-7 cells were co-exposed to the AhR ligands together with the CYP inhibitor, ellipticine [15].
• These enhancing effects of indirubin and indigo were not observed in AhR knock-out mice [23].
• CYP1A1 and CYP1A2 mRNAs were induced by as little as 1 pM of indirubin, whereas they were not induced by 10 pM of TCDD [12].
• In addition, indirubin induced marked IL-8 release by the cells during differentiation and the cells differentiated with indirubin had typical neutrophilic properties, deformed nuclei and granules [16].
• Our results suggest that indirubin and indigo act as inducers for cytochrome P450 1A1/2 mediated by AhR in mammals in vivo [23].

Analytical, diagnostic and therapeutic context of Indirubin

• Here we compared gene expression changes in HepG2 cells exposed to 10 nM of indirubin or TCDD using nylon-membrane-based cDNA arrays with 1176 genes to elucidate the toxic differences at the transcriptional level [12].
• The binding force between them was rather weak, as indirubin molecules were easily released during the precipitation with alcohol or the gel filtration [24].
• Evidence from TLC, NMR spectroscopy, absorption spectrum analysis and solubility behaviour suggested that the blue pigment was indigo and the pink pigment was indirubin, a structural isomer of indigo [25].

References