Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: KEGG:D02027 (Tranilast)
 205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tranilast, an antiallergic medication, is a very promising inhibitor of restenosis after balloon angioplasty. Tranilast can prevent the proliferation and migration of smooth muscle cells by activating the gene expression of p21, a strong cyclin/cyclin-dependent kinase (CDK) inhibitor, and by arresting cell growth at the G0/G1 phase. The signaling pathway of Tranilast in regulating p21 is to our best interest and is elucidated in the present study. The major emphasis was weighted on exploring the regulatory effects of Tranilast on promoter activity of p21. By serial deletion analysis, the sequence between -74 and -83 bp of the p21 promoter, previously identified as the transforming growth factor-beta (TGF-beta)-response element, was found sufficient, where as most of the promoter region 5' to -111 bp was found unnecessary for the transcriptional activation of p21 by both TGF-beta1 and Tranilast. Tranilast was also found to induce phosphorylation of Smad2 (a cytoplasmic signaling molecule essential for mediating TGF-beta signal transduction). Transfection of DeltakTbetaRII, a truncated form of TGF-beta type II receptor known to exert a dominant-negative effect on TGF-beta signaling, was found to suppress the signaling of both Tranilast and TGF-beta1 to a similar extent. These results suggested that induction of p21 by Tranilast might be closely related to TGF-beta signal transduction pathway.
 ...
PMID:Transcriptional activation of p21 by Tranilast is mediated via transforming growth factor beta signal pathway. 1628 27

Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid) is a synthetic compound that we have recently reported to inhibit transforming growth factor-beta1 (TGF-beta1)-induced tubulointerstitial fibrosis in the kidney. Connective tissue growth factor (CTGF) is recognized as a potent downstream mediator of TGF-beta1. Both proximal tubule cells (PTCs) and cortical fibroblasts (CFs) are considered to be responsible for the production of tubulointerstitial extracellular matrix (ECM). These studies were undertaken to assess the profibrotic effects of CTGF in an in vitro model of the human PTCs and CFs, and to determine whether tranilast is effective in limiting the in vitro matrix responses induced by CTGF. Primary cultures of PTCs and CFs were exposed to CTGF (20 ng/ml)+/-tranilast (100 microM). Cell hypertrophy and the secretion of the ECM proteins fibronectin and collagen IV were determined. The effects of tranilast on TGF-beta1-induced CTGF mRNA expression and on phosphorylation of Smad2 were determined. CTGF significantly induced cell hypertrophy, increased fibronectin, and collagen IV secretion in PTCs and CFs. In all cases, the CTGF-induced increase in ECM protein was inhibited in the presence of tranilast. Tranilast reduced CTGF mRNA and phosphorylation of Smad2, which were induced by TGF-beta1 in PTCs and CFs. These results suggest that tranilast is a potential effective antifibrotic compound in the kidney, exerting its effects via inhibition of TGF-beta1-induced CTGF expression and downstream activation of the Smad2 pathway in both PTCs and CFs.
 ...
PMID:Tranilast attenuates connective tissue growth factor-induced extracellular matrix accumulation in renal cells. 1652 48

Tranilast (N-[3,4-dimethoxycinnamonyl]-anthranilic acid) is a drug of low toxicity that is orally administered, and has been used clinically in Japan as an antiallergic and antifibrotic agent. Its antifibrotic effect is thought to depend on the inhibition of transforming growth factor-beta (TGF-beta). It has also been shown to exert antitumor effects, but its mode of action is unclear. Here, we explored the antitumor effects of tranilast in vitro and in vivo. Tranilast inhibited the proliferation of several tumor cell lines including mouse mammary carcinoma (4T1), rat mammary carcinoma stem cell (LA7), and human breast carcinoma (MDA-MB-231 and MCF-7). Tranilast blocked cell-cycle progression in vitro. In the highly metastatic 4T1 cell line, tranilast inhibited phospho-Smad2 generation, consistent with a blockade of TGF-beta signaling. It also inhibited the activation of MAP kinases (extracellularly regulated kinase 1 and 2 and JNK), which have been linked to TGF-beta-dependent epithelial-to-mesenchymal transition and, indeed, it blocked epithelial-to-mesenchymal transition. Although tranilast only partially inhibited TGF-beta production by 4T1 tumor cells, it potently inhibited the production of TGF-beta, interferon-gamma, IL-6, IL-10, and IL-17 by lymphoid cells, suggesting a general anti-inflammatory activity. In vivo, female BALB/c mice were inoculated with syngeneic 4T1 cells in mammary fat pads and treated with tranilast by gavage. Tranilast reduced (>50%) the growth of the primary tumor. However, its effects on metastasis were more striking, with more than 90% reduction of metastases in the lungs and no metastasis in the liver. Thus, tranilast has potential activity as an antimetastatic agent in breast cancer.
 ...
PMID:Tranilast inhibits the growth and metastasis of mammary carcinoma. 1932 72