tranilast and Uterine-Neoplasms

Uterine leiomyomas are a common disorder resulting in significant morbidity for women and substantial economic impact on the health care system. Current therapies include conservative surgery, hysterectomy, and hormonal therapy. Conservative surgical therapy often fails because of recurrence, and hysterectomy dramatically limits reproductive options. Radiologic therapies are associated with considerable risk of morbidity and mortality and are not likely to be compatible with reproduction. Hormonal therapies such as gonadotropin-releasing hormone (GnRH) analogues or progestins with or without estrogen are utilized by many patients, but long-term use of either is often responsible for unacceptable morbidity and hormonal therapies are not compatible with reproduction. Newer hormonal alternatives such as progesterone antagonists and selective agonists as well as "add-back" estrogen therapy in addition to GnRH analogues have been developed and show promise. However, no hormonal therapy that significantly alters estrogen and progesterone production or function is likely to be compatible with reproduction. Thus, it is important to develop novel nonhormonal therapies for medical treatment of leiomyomas. Other laboratories have evaluated pirfenidone, halofuginone, heparin, and interferon-alpha (IFN-alpha). Recent work in our laboratory suggests potential use of two additional classes of compounds, thiazolidinediones and tocopherol analogs. The rationale, evidence, and potential for the use of each of these compounds in the treatment of leiomyomas are discussed.

Topics: Bexarotene; Female; Heparin; Humans; Interferon-alpha; Leiomyoma; ortho-Aminobenzoates; Piperidines; Pyridones; Quinazolines; Quinazolinones; Reproduction; Tetrahydronaphthalenes; Thiazolidinediones; Tocopherols; Uterine Neoplasms

To determine the mechanism by which tranilast induces miR-200c expression in leiomyoma smooth muscle cells (LSMCs).. Experimental study.. Academic research laboratory.. Women undergoing hysterectomy for leiomyoma.. Blockade of RelA/p65.. Effects of tranilast and blockade of RelA/p65 on miR-200c expression.. Tranilast, an inflammation inhibitor, dose-dependently induced miR-200c in LSMCs and myometrium smooth muscle cells (MSMCs), with a more profound effect in LSMCs than in MSMCs. The treatment of LSMCs with Bay 117082, an inhibitor of IκB phosphorylation, further enhanced miR-200c induction by tranilast. The knockdown of RelA/p65 by small interfering RNA also induced miR-200c expression in LSMCs. Although tranilast had no effect on total RelA/p65 protein levels in LSMCs, it significantly induced RelA/p65 phosphorylation at S536 while reducing its activity as well as its nuclear translocation. ChIP assay indicated that tranilast reduces the binding ability of RelA/p65 to miR-200c promoter, resulting in miR-200c induction. Tranilast also inhibited interleukin-8 (IL8) expression in LSMCs. The induction of miR-200c by tranilast partially mediates the inhibitory effect of tranilast on the expression of IL8 and cyclin-dependent kinase 2 in LSMCs.. Induction of miR-200c by tranilast in LSMCs is mediated through a transcriptional mechanism involving inhibition of the nuclear factor κB signaling pathway. These results highlight the significance of inflammation in the pathogenesis of leiomyoma and the potential utility of antiinflammatory drugs for treatment of leiomyomas.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cyclin-Dependent Kinase 2; Female; Humans; Interleukin-8; Leiomyoma; MicroRNAs; Myocytes, Smooth Muscle; Myometrium; ortho-Aminobenzoates; Signal Transduction; Transcription Factor RelA; Tumor Cells, Cultured; Uterine Neoplasms

Tranilast (N-3,4-dimethoxycinnamoyl anthranilic acid) is an antiallergic agent with inhibitory effects on cell proliferation and extracellular matrix production. Here we assess the effect of tranilast on the expression of miR-29c and genes functionally involved in cell proliferation, fibrosis, and epigenetic regulation in isolated leiomyoma smooth muscle cells (LSMC). Tranilast significantly inhibited the rate of LSMC proliferation, which was associated with downregulation of cell cycle progression genes cyclin D1 (CCND1) and cyclin-dependent kinase 2 (CDK2) expression at messenger RNA and protein levels ( P < .05). Tranilast also suppressed the expression of collagen type I (COL1), collagen type III alpha 1 chain (COL3A1), the profibrotic cytokine, transforming growth factor β-3 (TGF-β3), DNA (cytosine-5)-methyltransferase 1 (DNMT1), and enhancer of zeste homolog 2 (EZH2), which regulate epigenetic status of gene promoters ( P < .05). Tranilast also significantly induced the expression of cellular and secreted miR-29c through downregulation of methylation status of miR-29c promoter ( P < .05). In addition, tranilast suppressed the activity of luciferase reporter containing 3'UTR of COL3A1 and CDK2, which are downstream targets of miR-29c ( P < .05). Knockdown of miR-29c expression attenuated the inhibitory effects of tranilast on COL3A1 and CDK2 protein expression ( P < .05). Collectively, these findings suggest that tranilast could have therapeutic potential as an inhibitory agent for leiomyoma growth and its associated symptoms.

Topics: Anti-Allergic Agents; Cell Line, Tumor; Cell Proliferation; Collagen Type I; Epigenesis, Genetic; Female; Fibrosis; Humans; Leiomyoma; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; ortho-Aminobenzoates; Uterine Neoplasms

To determine the effect of tranilast (an antiallergic drug known to suppress fibrosis or to stabilize mast cells) on extracellular matrix production in human leiomyoma and myometrial cells.. Laboratory study.. University-affiliated laboratory.. Seven premenopausal women who were admitted to the hospital for myomectomy or hysterectomy.. Cells were treated with tranilast (300 μM) for 48 hours to measure extracellular matrix and activin-A expression by real-time reverse-transcription polymerase chain reaction and/or immunocytochemistry.. The expression of fibronectin, collagen1A1, versican, and activin-A in myometrial and leiomyoma cells.. Tranilast decreased fibronectin, collagen 1A1, and versican messenger RNA (mRNA) expression in human primary leiomyoma cell culture. Similar results were found in an immortalized human leiomyoma cell line. Tranilast also decreased the mRNA expression of fibronectin, collagen 1A1, and versican in human primary myometrial cells. The reduced expression of fibronectin and collagen 1 were observed by immunocytochemistry as well. Tranilast also reduced profibrotic growth factor, activin-A mRNA expression in primary myometrial and leiomyoma cells.. Our results indicate that tranilast reduced fibronectin, collagen 1A1, versican, and activin-A expression in leiomyoma and myometrial cells, demonstrating its potential as an antifibrotic therapy for human leiomyomas.

Topics: Activins; Administration, Oral; Adult; Anti-Allergic Agents; Cell Line, Tumor; Collagen Type I; Collagen Type I, alpha 1 Chain; Extracellular Matrix; Female; Fibronectins; Fibrosis; Humans; Leiomyoma; Middle Aged; Myometrium; ortho-Aminobenzoates; RNA, Messenger; Tumor Cells, Cultured; Uterine Neoplasms; Versicans

Uterine leiomyoma is a mesenchymal tumor composed of smooth muscle cells with fibrous tissues and many mast cells. Tranilast is known to suppress fibrosis or to work as a mast cell stabilizer and is reported to inhibit proliferation of vascular smooth muscle cells. In this study, we examined the effects of tranilast on cultured human leiomyoma cells in vitro to evaluate whether this agent has the potential to inhibit the growth of uterine leiomyomas. Tranilast inhibited the proliferation of cultured leiomyoma cells in a dose-dependent manner without any cytotoxic effect or induction of apoptosis. In association with the inhibitory effect, tranilast induced the cyclin-dependent kinase (CDK) inhibitor p21(waf1) and tumor suppressor gene p53 and decreased CDK2 activity. These results suggest that tranilast arrests the proliferation of uterine leiomyoma cells at the G0/G1 phase, through the suppression of CDK2 activity via an induction of p21(waf1) and p53. Tranilast was concluded to be a potent agent to inhibit proliferative activity of uterine leiomyoma cells.

Topics: Blotting, Western; CDC2-CDC28 Kinases; Cell Cycle; Cell Division; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; Female; G1 Phase; Gene Expression Regulation; Genes, p53; Humans; Leiomyoma; Muscle, Smooth; Myometrium; ortho-Aminobenzoates; Protein Serine-Threonine Kinases; Tumor Cells, Cultured; Uterine Neoplasms