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 (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.
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PMID:Tranilast inhibits the growth and metastasis of mammary carcinoma. 1932 72

In the treatment of breast cancer, although a wide of choice of drugs and treatment modalities are available, drug resistance or drug toxicity poses a considerable challenge. Tranilast is a well tolerated drug used in the treatment of allergic disorders. Previous works in various models have shown that tranilast has the potential to be used as an anti-cancer drug. Hence, in this study using human breast cancer cell lines BT-474 and MDA-MB-231, we studied the effect of tranilast on cell growth, migration and ability to prevent colony formation in vitro, properties that are relevant to a possible therapeutic effect in breast cancer. We found that tranilast inhibits the growth of both breast cancer cell lines. In the cell migration experiments, the tumor cells exhibit significantly slower wound closure after tranilast treatment, as well as reduced migration using an insert system. Downregulation of MRTF-A, a global cytoskeleton regulator was observed after tranilast treatment. Additionally, tranilast treatment increased levels of cleaved PARP in both cell lines tested indicating a stimulation of apoptosis. A significant reduction in colony size and number was observed in soft agar clonogenic assays in both cell lines after tranilast treatment. BT-474 cells were more responsive to tranilast treatment compared to MDA-MB-231 cells, suggesting a difference in modes of action, or sensitivity, possibly related to their different receptor status. Based on these changes in cancer cell lines, we conclude that tranilast exerts effects that set a rationale for future preclinical studies in animal models of breast cancer.
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PMID:Tranilast treatment decreases cell growth, migration and inhibits colony formation of human breast cancer cells. 2104 Jul 20

It has been reported that CXCL12 binding to CXCR4 induces several intracellular signaling pathways, and enhances survival, proliferation, and migration of malignant cells. In the present study, we examined the effects of anti-estrogen tamoxifen and anti-allergic tranilast drugs as a single or in combination on invasion by two in-vitro invasion assays, wound-healing and matrigel invasion on MCF-7 and MDA-MB-231 human breast cancer cell lines. The mRNA expression levels of CXCR4 and CXCL12 were measured by quantitative real time-RT PCR and CXCL12 protein levels were evaluated by ELISA assay. The data showed that treatment with tamoxifen and tranilast as a single or in combination resulted in decreased CXCR4 and CXCL12 mRNA and CXCL12 protein expression levels. Both in-vitro invasion assays markedly showed synergistic effect of tamoxifen when combined with tranilast drug. Either ER-positive or ER-negative breast cancer cells were sensitive to this combination therapy. In conclusion, Tranilast increases antimetastatic effect of tamoxifen. The synergistic effect of tranilast is not estrogen dependent; however tamoxifen may sensitize the cells for the action of tranilast. The data also support the importance of the CXCR4/CXCL12 interaction in breast cancer metastasis, and further suggest that CXCR4 and CXCL12 are critical targets for tamoxifen and tranilast in combination or alone.
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PMID:The Effects of Tamoxifen in Combination with Tranilast on CXCL12-CXCR4 Axis and Invasion in Breast Cancer Cell Lines. 2523 65

Modern High-Throughput Screening (HTS) techniques allow to determine in vitro bioactivity of tens of thousands of chemicals within a relatively short period of time and tested compounds are usually interpreted as either active or inactive. The interpretation is mostly based on the assumption of monotonic dose-response. This approach ignores potential abnormal dose-response relationships, such as non-monotonic dose-response (NMDR). NMDR presents a serious challenge to toxicologists and pharmacologists, since they undermine the usefulness of such concepts as lowest-observed-adverse-effect level (LOAEL) and no-observed-adverse-effect level (NOAEL). The possible presence of the NMDR in Androgen receptor (AR) agonism was examined for a structurally diverse set of chemicals (~8 300 unique compounds) from Tox21 project library. The source of activity data is Tox21 AR agonism luciferase-based HTS on the MDA-MB-453 cell line. The examination of curve fitting for 35,328 dose-response data entries was based on modified version of existing criteria for determination of NMDR. The bias that arises from compounds' cytotoxicity and interference with firefly luciferase protein was also studied. The examination has shown evidence of NMDR for several compounds, including known AR antagonists (e. g. Cyproterone acetate) and other known endocrine disruptors (e. g. Tranilast). Compounds were divided into 3 groups based on chemical class, known biological activity profile and the shape of dose-response curve. The challenges of using HTS data to determine NMDR and benefits of this analysis are discussed.
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PMID:Examining the evidence of non-monotonic dose-response in Androgen Receptor agonism high-throughput screening assay. 3321 76