Tranilast inhibits the proliferation of human coronary smooth muscle cell through the activation of p21waf1

Abstract-Cardiac allograft vasculopathy is a major complication after cardiac transplantation, often limiting long-term recipient survival. N- (3,anthranilic acid (tranilast) inhibits cyclin-dependent kinase activity through p21 Waf1/Cip1 induction and arrests vascular smooth muscle cell proliferation in vitro. We tested a hypothesis that tranilast inhibits the vasculopathy characterized by diffuse intimal thickening in a murine heart transplantation model. Hearts from DBA/2 mice were heterotopically transplanted into B10.D2 mice as allografts. Oral administration of tranilast started 3 days before transplantation at doses of 550 or 1040 mg/kg per day until the animals were killed. Cardiac allograft vasculopathy was defined as luminal stenosis caused by neointimal formation. The percentage of luminal stenosis and cardiac rejection were analyzed 14 and 28 days after transplantation. Tranilast administration was associated with a marked reduction in luminal occlusion but with no significant effect on cardiac rejection. Immunohistochemical study of the tranilast-treated graft coronary arteries revealed enhancement of p21Waf1/Cip1 and decreased expression of proliferating cell nuclear antigen in the neointima. The significant reduction in allograft vasculopathy concomitant with the enhancement of p21Waf1/Cip1 indicates that tranilast has an antiproliferative effect that could be applicable to clinical treatment of cardiac allograft vasculopathy.

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“…39 Moreover, it has been shown to suppress the neointima/media area ratio by increased expression of p21…”

Section: Izawa Et Al Tranilast Inhibits Cardiac Allograft Vasculopathymentioning

confidence: 99%

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Izawa

Suzuki²,

Takahashi³

et al. 2001

ATVB

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“…14,15 This is illustrated by the observation that the HDAC-inhibitor TSA was found to inhibit SMC proliferation via induction of p21WAF1. 16 Activity of p21WAF1 is known to induce cell-cycle arrest in vascular SMCs, [17][18][19][20] and A20, a NFκB-dependent gene that has been shown to inhibit proliferation of vascular SMCs via increased expression of p21WAF1, has been shown to prevent neointima formation after balloon angioplasty in a rat model of carotid artery stenosis. 21 Histone acetylation modifications have also been shown to play a role in the expression of matrix metalloproteinases (MMPs), critical mediators in vascular remodelling.…”

mentioning

confidence: 99%

Epigenetic histone acetylation modifiers in vascular remodelling – new targets for therapy in cardiovascular disease

Pons

Jukema²

2008

NHJL

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“…Previous report showed that the concentration of tranilast in human plasma was estimated at 30-300 μM in case of daily oral intake of 600 mg tranilast for the treatment of allergic patients, suggesting the reasonable setting of tranilast concentration in the present in vitro study (22). Tranilast is usually taken orally and found to have few side effects except eosinophilic cystitis (33).…”

Section: Discussionmentioning

confidence: 77%

“…This drug is taken orally and exerts the drug effect against allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis (17,18). It has been reported that this compound is also effective in disease with excessive fibrosis such as keloid, because it inhibits fibroblast proliferation leading to the suppression of collagen accumulation (19)(20)(21)(22)(23)(24)(25). Recently, several reports showed that tranilast inhibits the proliferation of several cancer cell lines (26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Tranilast strongly sensitizes pancreatic cancer cells to gemcitabine via decreasing protein expression of ribonucleotide reductase 1

Mitsuno

Kitajima²,

Ohtaka³

et al. 2009

Int J Oncol

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Abstract. Gemcitabine (Gem) is a dFdC analogue with activity against several solid tumors. Gem is intracellularly phosphorylated by dCK, leading to the production of the metabolite dFdCDP. dFdCDP exhibits the cytotoxic effect by inactivating ribonucleotide reductase larger subunit 1 (RRM1), which is a rate limiting enzyme for de novo DNA synthesis. To date, RRM1 expression is believed to determine sensitivity to Gem in pancreatic and non-small cell lung cancer. In the present study, we found that an anti-allergic drug, tranilast strongly enhanced the sensitivity of pancreatic cancer cell line KP4 to Gem. In growth inhibition assay, 100 μM of tranilast plus 1 μM of Gem more strongly suppressed the growth of KP4 at 12.7-fold in IC 50 than single Gem treatment, while this compound no longer affected the sensitivity to other drugs such as 5-fluorouracil, irinotecan or paclitaxel. FACS and TUNEL analysis demonstrated the increased apoptotic population in KP4 cells under tranilast plus Gem, compared with single Gem treatment. In Western blot analysis, tranilast treatment decreased RRM1 expression at protein level with dose-dependency in KP4 cells. Proteasome inhibitor MG132 disturbed the reduction of RRM1 expression in tranilast treated KP4 cells, indicating protein degradation by the activated proteasome. Transfection using siRNA against RRM1 increased the sensitivity of KP4 to Gem, suggesting that RRM1 suppression is an important step in increasing Gem efficacy. Finally, we demonstrated that tranilast reduced RRM1 protein and increased Gem efficacy in 4 other pancreatic cell lines. In a future, a novel chemotherapeutic strategy by Gem along with tranilast might improve Gem efficacy against pancreatic cancer.

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Tranilast inhibits the proliferation of human coronary smooth muscle cell through the activation of p21waf1

Cited by 36 publications

References 16 publications

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Epigenetic histone acetylation modifiers in vascular remodelling – new targets for therapy in cardiovascular disease

Tranilast strongly sensitizes pancreatic cancer cells to gemcitabine via decreasing protein expression of ribonucleotide reductase 1

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Tranilast inhibits the proliferation of human coronary smooth muscle cell through the activation of p21waf1

Cited by 36 publications

References 16 publications

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Epigenetic histone acetylation modifiers in vascular remodelling – new targets for therapy in cardiovascular disease

Tranilast strongly sensitizes pancreatic cancer cells to gemcitabine via decreasing protein expression of ribonucleotide reductase 1

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Product

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Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model