Indirubin Enhances Tumor Necrosis Factor-induced Apoptosis through Modulation of Nuclear Factor-κB Signaling Pathway

Sethi, Gautam; Ahn, Kwang Seok; Sandur, Santosh K.; Lin, Xin; Chaturvedi, Madan M.; Aggarwal, Bharat B.

doi:10.1074/jbc.m602627200

Cited by 111 publications

(69 citation statements)

References 69 publications

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“…Consistent with several previous reports that indirubin-3 0 -monoxime inhibits intracellular targets other than FGFR1 (Hoessel et al, 1999;Adachi et al, 2001;Leclerc et al, 2001;Xie et al, 2004;Sethi et al, 2006), we found that in NIH/3T3 cells indirubin-3 0 -monoxime inhibited the phosphorylation of CDK2 and Rb, a CDK-regulated protein involved in regulation of cellcycle progression. However, the concentration of indirubin-3 0 -monoxime required to inhibit Rb and CDK2 phosphorylation was higher for FCS-stimulated cells than for FGF-1-stimulated cells, that is, 20 and 5 mM, respectively.…”

Section: Discussionsupporting

confidence: 93%

“…Additionally, it was recently reported that indirubin derivatives were able to block Stat3 signaling by inhibiting the Src kinase activity and in this way induce apoptosis in human cancer cells (Nam et al, 2005), and also, bind to and inhibit glycogen synthetase kinase-3 (Leclerc et al, 2001;Polychronopoulos et al, 2004), aryl hydrocarbon receptor (Adachi et al, 2001), muscle glycogen phosphorylase b (Kosmopoulou et al, 2004) and c-Jun NH2-terminal kinase (JNK) (Xie et al, 2004). More recently, indirubin-3 0 -monoxime was found to inhibit the activation of nuclear factor-kB resulting in enhancement of apoptosis induced by tumor necrosis factors in human leukemic cells (Sethi et al, 2006).…”

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: Discussionsupporting

confidence: 93%

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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“…Cytotoxicity was assayed by the modified tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, as described previously (72).…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Sethi

Ahn

Aggarwal

2008

Molecular Cancer Research

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300

218

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Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-KB (NF-KB) signaling, we investigated in detail the effect of this quinone on NF-KB pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor -induced NF-KB activation in a dose-and time-dependent manner and inhibited NF-KB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-KB activation correlated with sequential inhibition of the activation of IKBA kinase, IKBA phosphorylation, IKBA degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-KB -dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-KB -regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-KB activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.

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“…Cytotoxicity Assay Cytotoxicity was assayed by the modified tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay as described elsewhere (20).…”

Section: Methodsmentioning

confidence: 99%

“…To determine the effect of pinitol on TNF-dependent InBa phosphorylation and degradation, cytoplasmic extracts were prepared as described elsewhere (20) from cells that had been pretreated with pinitol and then exposed to TNF for various times. Cytoplasmic protein (30 Ag) was resolved by 10% SDS-PAGE, transferred to a nitrocellulose membrane, blocked with 5% nonfat milk, and probed with specific antibodies against InBa and phosphorylated InBa.…”

Section: Western Blot Analysismentioning

confidence: 99%

Pinitol targets nuclear factor-κB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis

Sethi

Ahn

Sung

et al. 2008

Molecular Cancer Therapeutics

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123

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Pinitol (3-O-methyl-chiroinositol), a component of traditional Ayurvedic medicine (talisapatra), has been shown to exhibit anti-inflammatory and antidiabetic activities through undefined mechanisms. Because the transcription factor nuclear factor-KB (NF-KB) has been linked with inflammatory diseases, including insulin resistance, we hypothesized that pinitol must mediate its effects through modulation of NF-KB activation pathway. We found that pinitol suppressed NF-KB activation induced by inflammatory stimuli and carcinogens. This suppression was not specific to cell type. Besides inducible, pinitol also abrogated constitutive NF-KB activation noted in most tumor cells. The suppression of NF-KB activation by pinitol occurred through inhibition of the activation of IKBA kinase, leading to sequential suppression of IKBA phosphorylation, IKBA degradation, p65 phosphorylation, p65 nuclear translocation, and NF-KB-dependent reporter gene expression. Pinitol also suppressed the NF-KB reporter activity induced by tumor necrosis factor receptor (TNFR)-1, TNFR-associated death domain, TNFR-associated factor-2, transforming growth factor-B -activated kinase-1 (TAK-1)/TAK1-binding protein-1, and IKBA kinase but not that induced by p65. The inhibition of NF-KB activation thereby led to down-regulation of gene products involved in inflammation (cyclooxygenase-2), proliferation (cyclin D1 and c-myc), invasion (matrix metalloproteinase-9), angiogenesis (vascular endothelial growth factor), and cell survival (cIAP1, cIAP2, X-linked inhibitor apoptosis protein, Bcl-2, and Bcl-xL). Suppression of these gene products by pinitol enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNFinduced cellular invasion. Our results show that pinitol inhibits the NF-KB activation pathway, which may explain its ability to suppress inflammatory cellular responses.

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Indirubin Enhances Tumor Necrosis Factor-induced Apoptosis through Modulation of Nuclear Factor-κB Signaling Pathway

Abstract: Although indirubin is known to exhibit anti-cancer and antiinflammatory activities, very little is known about its mechanism of action. In this study, we investigated whether indirubin mediates its effects through interference with the NF-B path-

Cited by 111 publications

References 69 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

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Pinitol targets nuclear factor-κB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis

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