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Rich66 03-31-2009 02:28 PM

Tranilast inhibits the growth and metastasis of mammary carcinoma.
<dl class="AbstractPlusReport"><dt class="head">Anticancer Drugs. 2009 Mar 24. [Epub ahead of print]<script language="JavaScript1.2"><!-- var Menu19322072 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1932 2072&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Tranilast inhibits the growth and metastasis of mammary carcinoma.
</dd><dd class="abstract">
</dd><dd class="abstract">FULL TEXT
</dd><dd class="abstract">
<!--AuthorList-->Chakrabarti R, Subramaniam V, Abdalla S, Jothy S, Prudʼhomme GJ.
aDepartment of Laboratory Medicine and Li Ka Shing Knowledge Institute, St Michael's Hospital bDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
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: 19322072 [PubMed - as supplied by publisher</dd></dl>

Anticancer Drugs. 2010 Feb 6. [Epub ahead of print]
Tranilast inhibits cell proliferation and migration and promotes apoptosis in murine breast cancer.

Subramaniam V, Chakrabarti R, Prudʼhomme GJ, Jothy S.
aDepartment of Laboratory Medicine and Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital bDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
The malignant transformation of breast epithelium involves a number of cellular pathways, including those dependent on signaling from TGF beta. Tranilast [N-(3, 4-dimethoxycinnamonyl)-anthranilic acid] is a drug that is used in Japan to control allergic disorders in patients, and its mechanism of action involves TGF beta. In view of the multiple roles of TGF beta in tumor progression, we hypothesized in this study that tranilast impacts cell proliferation, apoptosis, and migration. Using the mouse breast cancer cell line 4T1, our studies showed that tranilast increases AKT1 phosphorylation and decreases ERK1/2 phosphorylation. Alterations in the cell cycle mediators' cyclin D1, p27, cyclin A, pRB, cyclin B, and Cdc2 were observed after exposure to tranilast, favoring cell arrest beyond the G1/S phase. Tranilast reduced tumor cell proliferation even when it was amplified by exogenous TGF beta. TGF beta-neutralizing antibody did not cause a significant decrease in cell proliferation. Tranilast treatment upregulates p53, induces PARP cleavage in vitro, consistent with a promotion of tumor cell apoptosis. TGF beta-neutralizing antibody downregulates endoglin and matrix metalloproteinases (MMP)-9 levels in vitro indicating that the tranilast effect is mediated through TGF beta modulation. Tranilast treatment results in the inhibition of cell migration and invasion. Western blot analysis of tumor lysates from tranilast-treated mice shows decreased levels of TGF beta1, endoglin, and significantly higher levels of p53 and cleaved PARP. Cleaved caspase 3 expression is significantly elevated in tranilast-treated mouse breast tumors. To conclude, tranilast induces cellular and molecular changes in murine breast cancer that can be exploited in preclinical therapeutic trials.

Int J Oncol. 2010 Feb;36(2):341-9.
Tranilast strongly sensitizes pancreatic cancer cells to gemcitabine via decreasing protein expression of ribonucleotide reductase 1.


Mitsuno M, Kitajima Y, Ohtaka K, Kai K, Hashiguchi K, Nakamura J, Hiraki M, Noshiro H, Miyazaki K.
Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
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 microM of tranilast plus 1 microM of Gem more strongly suppressed the growth of KP4 at 12.7-fold in IC50 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.

PMID: 20043067 [PubMed - in process]

PLoS One. 2010 Nov 3;5(11):e13831.
Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist.

Prud'homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V, Jothy S.

Department of Laboratory Medicine and Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Canada. prudhommeg@smh.ca




Cancer stem cells (CSCs) have increased resistance to cancer chemotherapy. They can be enriched as drug-surviving CSCs (D-CSCs) by growth with chemotherapeutic drugs, and/or by sorting of cells expressing CSC markers such as aldehyde dehydrogenase-1 (ALDH). CSCs form colonies in agar, mammospheres in low-adherence cultures, and tumors following xenotransplantation in Scid mice. We hypothesized that tranilast, a non-toxic orally active drug with anti-cancer activities, would inhibit breast CSCs.
We examined breast cancer cell lines or D-CSCs generated by growth of these cells with mitoxantrone. Tranilast inhibited colony formation, mammosphere formation and stem cell marker expression. Mitoxantrone-selected cells were enriched for CSCs expressing stem cell markers ALDH, c-kit, Oct-4, and ABCG2, and efficient at forming mammospheres. Tranilast markedly inhibited mammosphere formation by D-CSCs and dissociated formed mammospheres, at pharmacologically relevant concentrations. It was effective against D-CSCs of both HER-2+ and triple-negative cell lines. Tranilast was also effective in vivo, since it prevented lung metastasis in mice injected i.v. with triple-negative (MDA-MB-231) mitoxantrone-selected cells. The molecular targets of tranilast in cancer have been unknown, but here we demonstrate it is an aryl hydrocarbon receptor (AHR) agonist and this plays a key role. AHR is a transcription factor activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatic hydrocarbons and other ligands. Tranilast induced translocation of the AHR to the nucleus and stimulated CYP1A1 expression (a marker of AHR activation). It inhibited binding of the AHR to CDK4, which has been linked to cell-cycle arrest. D-CSCs expressed higher levels of the AHR than other cells. Knockdown of the AHR with siRNA, or blockade with an AHR antagonist, entirely abrogated the anti-proliferative and anti-mammosphere activity of tranilast. Thus, the anti-cancer effects of tranilast are AHR dependent.

We show that tranilast is an AHR agonist with inhibitory effects on breast CSCs. It is effective against CSCs of triple-negative breast cancer cells selected for anti-cancer drug resistance. These results suggest it might find applications in the treatment of breast cancer.
<dl class="rprtid"><dt>PMID:</dt><dd>21072210</dd><dd> [PubMed - indexed for MEDLINE] </dd><dd>
</dd><dt>PMCID: PMC2972222</dt></dl>

Inhibition occurred at tranilast concentrations ≥100 然, and at 400 然 no mammospheres were seen. Tranilast reduced cell survival in these cultures, but even at the highest concentration (400 然) almost 50% of cells survived after 7 d in culture (Fig. S1B). Note that at concentrations that can be achieved pharmacologically (100–200 然) some spheres still formed (although they were smaller), suggesting survival of sphere-forming cells.


Figure 5Tranilast inhibits mammosphere formation by mitoxantrone-selected MDA-MB-231 cells.

We compared the effects of tranilast with paclitaxel and etoposide at various concentrations. In Fig. 5A,B, the results obtained with the highest concentrations of either paclitaxel (60 然) or etoposide (40 然) tested are shown. Lower concentrations were less effective (not shown). As seen in Fig. 5A, pharmacological concentrations of tranilast (100–200 然) were more effective than these drugs at reducing the number of mammospheres.

Tranilast inhibits the following: cell cycling, TGF-β activity, MAPK signaling, epithelial-to-mesenchymal transition (EMT), cell migration and invasion. In vivo, it has prominent anti-metastatic effects [12]. Here we show that tranilast strongly inhibits CSCs in colony forming assays and mammosphere formation assays, at pharmacologically relevant concentrations. Tranilast was highly active at inhibiting mammosphere formation by D-CSCs, and dissociating formed mammospheres. It was effective in vivo, preventing metastasis to the lungs following i.v. injection of MDA-MB-231 mitoxantrone-selected cells.The molecular target(s) of tranilast in cancer have been unclear, but we demonstrate here that it is an aryl hydrocarbon receptor (AHR) agonist. The AHR is a transcription factor known principally as a receptor for toxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [15], but it has other functions [16] and appears to exert some anti-cancer effects [17], [18]. We show that tranilast binds to the AHR, induces its translocation to the nucleus, and stimulates CYP1A1 expression (a classic marker of AHR activity). D-CSCs expressed increased amounts of AHR. Knockdown of the AHR with siRNA, or addition of an AHR antagonist to cultures, both abolished the activity of tranilast in vitro. Thus, the activity of tranilast appears to be highly AHR dependent.
We also show that tranilast is effective at inhibiting CSCs of triple-negative (ER−/PR−/HER-2−) breast cancer cell lines (MDA-MB-231, SUM149 and SUM159) or a triple-positive cell line (ER+/PR+/HER-2+) (BT474). This is particularly relevant because triple-negative cells have lacked a distinct molecular target and their treatment is problematic. Recent studies suggest that the AHR is an excellent target for breast cancer therapy [17], [18], and tranilast appears to be an exceptional drug for this purpose.

Active ingredient in oats?

J Agric Food Chem. 2009 Nov 25;57(22):10619-24.
In vitro antioxidant activity and antigenotoxic effects of avenanthramides and related compounds.

Lee-Manion AM, Price RK, Strain JJ, Dimberg LH, Sunnerheim K, Welch RW.
Northern Ireland Centre for Food and Health, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, United Kingdom.
Avenanthramides are substituted N-cinnamoylanthranilic acids, with hydroxycinnamic acid and anthranilic acid moieties. These alkaloid phenols, which are unique to oats, may confer health benefits via antioxidant or other mechanisms. Synthetic avenanthramides, hydroxycinnamic acids, Tranilast, and ascorbic acid were evaluated for antioxidant activity using two assays, DPPH (2,2-diphenyl-1-picrylhydrazyl) and FRAP (ferric reducing antioxidant potential), and for antigenotoxicity using the Comet assay with stressed human adenocarcinoma colon cells. Of all the compounds tested, N-(3',4'-dihydroxy-(E)-cinnamoyl)-5-hydroxyanthranilic acid (2c), an abundant oat avenanthramide, generally had the highest activity in all three assays. The drug Tranilast showed antigenotoxic effects, but not antioxidant activity, suggesting that antigenotoxicity is not dependent on antioxidant effects. Overall, results show that avenanthramides exert antioxidant and antigenotoxic activities that are comparable to those of ascorbic acid and which have the potential to exert beneficial physiological effects.

PMID: 19874025 [PubMed - in process]

Br J Pharmacol. 2010 Jan 8. [Epub ahead of print]
The anti-allergic compound tranilast attenuates inflammation and inhibits bone destruction in collagen-induced arthritis in mice.

Shiota N, Kovanen PT, Eklund KK, Shibata N, Shimoura K, Niibayashi T, Shimbori C, Okunishi H.
Department of Pharmacology, Shimane University School of Medicine, Shimane, Japan.
Background and purpose: Recent findings suggest the importance of mast cells in the pathogenesis of rheumatoid arthritis and their potential as a therapeutic target. Tranilast is an anti-allergic compound with a potent membrane-stabilizing effect on mast cells and a wide range of anti-inflammatory effects, thus may be advantageous in the treatment of arthritis. Here, we have evaluated the effects of tranilast on the progression of collagen-induced arthritis in mice. Experimental approach: Tranilast (400 mg.kg(-1).day(-1)) was orally administered for 8 weeks to mice with established collagen-induced arthritis. Arthritis was assessed by clinical signs and X-ray scores. In paw tissue, the numbers of mast cells and osteoclasts were measured by histological analysis, and several inflammatory factrs were assessed by RT-PCR and Western blot analysis. Key results: TNF-alpha-positive mast cells were present extensively throughout the inflamed synovium of vehicle-treated arthritic mice, with some mast cells in close proximity to osteoclasts in areas of marked bone and cartilage destruction. Tranilast significantly reduced clinical and X-ray scores of arthritis and decreased numbers of TNF-alpha-positive mast cells and mRNA levels of TNF-alpha, chymase (mouse mast cell protease 4), tryptase (mouse mast cell protease 6), stem cell factor, interleukin-6, cathepsin-K, receptor activator of nuclear factor-kappaB, and of receptor activator of nuclear factor-kappaB-ligand, but increased interleukin-10 mRNA level in paws of arthritic mice. Osteoclast numbers were decreased by treatment with tranilast. Conclusions and implications: Tranilast possesses significant anti-rheumatic efficacy and, probably, this therapeutic effect is partly mediated by inhibition of mast cell activation and osteoclastogenesis.

PMID: 20067475 [PubMed - as supplied by publisher]

Rich66 03-31-2009 02:33 PM

A link to Tranilast description:

chrisy 03-31-2009 06:58 PM

Rich, thanks for posting this - how do you find all this stuff????

There are so many things out there - and it's very encouraging when they find out that old dogs may be able to learn new, important, tricks!

Rich66 03-31-2009 07:03 PM

Why Google when you can Pubble:


Now..how do we get Walgreens to carry this stuff?

Rich66 04-05-2009 12:41 PM

Anyone ask their oncs about this?

Rich66 05-24-2009 02:31 PM

Wow...expensive stuff:


US company working on non-cancer trials of Tranilast:

trial for arthrtitis (inflammation link?) combined with methotrexate:

Rich66 05-24-2009 02:49 PM

<dl class="AbstractPlusReport"><dt class="head">1: Hinyokika Kiyo. 1992 Aug;38(8):953-6.<script language="JavaScript1.2"><!-- var Menu1384294 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=1384294&ordinal pos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Re sultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstract Plus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=1384294&ordi nalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstr actPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1384 294&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubme d.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed _RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> [A case of tranilast-induced cystitis with transient ECG changes]

[Article in Japanese]

<!--AuthorList-->Fujii Y, Tosaka A, Ajima J, Oka K, Koide T.
Division of Urology, Kanto Central Hospital.
A case of tranilast (Rizaben)-induced cystitis accompanied with possibly hypereosinophilic heart syndrome was described. A 75-year-old male, who had been taking tranilast for allergic dermatitis for two months, was admitted for severe bladder stimulating symptoms which was unresponsive to antibiotic therapies. Clinical examination revealed tenderness of the prostate, aseptic pyuria, eosinophilia, liver dysfunction and electrocardiographic disorders including atrial fibrillation, T-wave inversions and lowered ST segment without any cardiac symptoms. Cystitis symptoms, pyuria, eosinophilia and liver dysfunction improved within several days after discontinuance of tranilast, and ST-T changes on ECG gradually normalized within a few months. Tranilast-induced cystitis has been demonstrated as a type of eosinophilic cystitis. Since pathologic findings of eosinophilic cystitis and hypereosinophilic heart syndrome are markedly similar and all symptoms and signs disappeared after deprivation of tranilast, it appears likely that eosinophilic inflammation was induced to the heart, liver, bladder and prostate of the current patient by tranilast.
PMID: 1384294 [PubMed - indexed for MEDLINE]
</dd><dd class="ad"> Related articles


Rich66 05-24-2009 08:23 PM

Tranilast inhibits the growth and metastasis of mammary carcinoma
Chakrabarti, Rabindranath; Subramaniam, Venkateswaran; Abdalla, Salma; Jothy, Serge; Prud'homme, G廨ald J.
Anti-Cancer Drugs, June 2009,20(5):334-345
Preclinical Reports
http://journals.lww.com/anti-cancerd...s/type_img.gifFig. 6
Fig. 6 Tranilast inhibits metastasis of 4T1 mammary carcinoma to the lungs and liver. Mice were transplanted with 4T1 cells and treated with tranilast by gavage, as in Fig. 5 (eight mice in each group). On day 28 of treatment, the mice were killed and the lungs and liver were collected and examined histologically. (a) Number of tumors per lung section (▪, vehicle; □, tranilast), expressed as the mean崆D (n = 8). (b) Histological sections of lungs showing metastatic tumors. As shown here, the tranilast-treated mice had smaller tumors than the vehicle-treated group (marked areas). (c) The area of each metastatic tumor lesions was measured in each lung section by a morphometric method. The mean area per metastatic tumor was significantly higher in the vehicle group than in the tranilast group (PAnti-Cancer Drugs, June 2009,20(5)

http://journals.lww.com/anti-cancerd...s/type_img.gifFig. 3
Fig. 3 Tranilast inhibits TGF-β1-induced epithelial-to-mesenchymal transition (EMT) in 4T1 cells. (a) 4T1 cells were attached to cover slips and cultured for 48 h in the presence and absence of tranilast (800 μmol/l) and TGF-β1 (2 ng/ml). The cells were stained for F-actin with Alexa Fluor 568-conjugated phalloidin. Photographs were taken at a magnification of 400. Addition of TGF-β1 to the cultures induced EMT as revealed from massive F-actin fiber organization and this was markedly reduced by tranilast treatment. Four experiments yielded similar results. Tranilast also inhibited EMT at a concentration of 200 μmol/l, but the effect was less marked (data not shown). (b) 4T1 cells were deprived of serum for 24 h followed by culture in complete medium in the presence or absence of vehicle (dimethyl sulfoxide) or tranilast (800 μmol/l) for 48 h. The cells were lysed and analyzed for vimentin (mesenchymal marker) by western blot as in Materials and methods. Upper panel: picture of the western blot; lower panel: densities of vimentin bands as percentage of β-actin controls. Tranilast treatment drastically reduced the vimentin level. Two experiments yielded similar results.
Anti-Cancer Drugs, June 2009,20(5)

http://journals.lww.com/anti-cancerd...s/type_img.gifFig. 4
Fig. 4 Effect of tranilast on cytokine release/production by spleen cells and 4T1 cell. (a) CD4+25- and CD8+ T cells were isolated from C57BL/6 mice and stimulated with plate-bound anti-CD3 and anti-CD28 mAbs, in the presence or absence of tranilast for 48 h. Then the supernatant was acidified for TGF-β1 activation, and TGF-β1 levels in the culture supernatant were measured by enzyme-linked immunosorbent assay. The control T cells (without tranilast) generated TGF-β1 levels of 838.7 pg/ml in CD4+ cells and 395.2 pg/ml in CD8+ T cells (mean崆D; n = 3). At all concentrations, tranilast significantly inhibited the production of TGF-β1 by both cell types (PAnti-Cancer Drugs, June 2009,20(5)

http://journals.lww.com/anti-cancerd...s/type_img.gifFig. 1
Fig. 1 Effect of tranilast on the growth of breast cancer and other tumor cell lines in vitro. (a) Various tumor cells (LA7, 4T1, MDA-MB-231, LLC, EL4, MCF-7 cells) were allowed to attach to the wells (10103 cells/well) of a flat-bottom 96-well plate. Various concentrations of tranilast were added to the cells and cultured for 48 h. Cell growth was monitored by MTT assay. Growth or proliferation in all cell lines was suppressed, with LA7 being the most sensitive. The suppression of cell growth was not accompanied by cytotoxicity (data not shown). Results are the mean崆D of three separate experiments. (b) 4T1 cells were cultured for 24 h in serum-free medium, followed by the culture in complete medium in the presence or absence of dimethyl sulfoxide (DMSO) or tranilast for 24 h. Then cell-cycle progression was analyzed by flow cytometry. The percentage of cells in the G1, S, or G2 phases is reported inside each histogram. Tranilast inhibited cells cycle in the S-phase at 200 μmol/l, and primarily at the G1 phase at 800 μmol/l. Two experiments yielded similar results.
Anti-Cancer Drugs, June 2009,20(5)

http://journals.lww.com/anti-cancerd...s/type_img.gifFig. 5
Fig. 5 Tranilast inhibits the growth of transplanted 4T1 mammary carcinoma. 4T1 cells were transplanted orthotopically in mammary fat pads of 6-week-old female BALB/c mice (eight mice in each group). Tranilast was administered by gavage at a dose of 300 mg/kg body weight from day 0 (day of cancer cell transplantation) to the end of the treatment. Tumor volume (mean崆D, n = 8) over time is reported (▪, vehicle group; □, tranilast group). At all time points, tumor size in the tranilast group was significantly lower than in the vehicle group (PAnti-Cancer Drugs, June 2009,20(5)

http://journals.lww.com/anti-cancerd...s/type_img.gifFig. 2
Fig. 2 Tranilast inhibits TGF-β1-induced Smad2 phosphorylation and serum-induced extracellularly regulated kinase 1 and 2 (ERK1/2) phosphorylation in 4T1 cells. (a) 4T1 cells were attached directly to microscopic slides and incubated for 20 h in the presence of TGF-β1 (2 ng/ml), tranilast (800 μmol/l), or both, and stained for phosphorylated Smad2 (pSmad2) as described in Materials and methods. The cells receiving only vehicle [dimethyl sulfoxide (DMSO)] treatment served as control. TGF-β1 increased nuclear staining for pSmad2, and this was almost completely blocked by tranilast. Photomicrographs were taken at 400 magnification. Four experiments yielded similar results. (b) 4T1 cells were deprived of serum for 24 h followed by culture in complete medium in the presence or absence of vehicle (DMSO) or tranilast (800 μmol/l) for 24 h. The cells were lysed and analyzed for pSmad2 by western blotting. Upper panel: picture of the western blot; lower panel: densities of pSmad2 bands as percentage of β-actin controls. There is approximately 38% reduction in the level of pSmad2. This is one of the two experiments that yielded similar results. (c) 4T1 cells were grown in flat-bottom 96-well plates overnight, followed by serum deprivation for 24 h. After that, cells were cultured for another 24 h in complete medium in the presence of DMSO (control) or 800 μmol/l tranilast. The level of phosphorylated and total ERK1/2 and JNK were measured by CASE enzyme-linked immunosorbent assay, and the relative extent of phosphorylation was calculated, according to the supplier's protocol. The extent of phosphorylation refers to the proportion (fraction) of the total protein (ERK or JNK) that is phosphorylated. Results are the mean崆D of three separate experiments. Tranilast significantly (PAnti-Cancer Drugs, June 2009,20(5)

Rich66 06-14-2009 11:03 AM

<dl class="AbstractPlusReport"><dt class="head">1: J Nippon Med Sch. 2002 Jun;69(3):224-34.http://www.ncbi.nlm.nih.gov/corehtml...go.jp-logo.gif <script language="JavaScript1.2"><!-- var Menu12068313 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=12068313&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=12068313&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["Cited in PMC" , "window.top.location='http://www.pubmedcentral.gov/tocrender.fcgi?action=cited&tool=pubmed&pubmedid=1 2068313&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstra ctPlus&ordinalpos=1' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1206 8313&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Anti-tumor effect of N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) on experimental pancreatic cancer.

<!--AuthorList-->Hiroi M, Onda M, Uchida E, Aimoto T.
First Department of Surgery, Nippon Medical School, Japan. hiroi-surg1@nms.ac.jp
The anti-tumor effect of N- [3,4-dimethoxycinnamoyl] -anthranilic acid (tranilast) was examined in experimental pancreatic cancer. Proliferation of PGHAM-1 cells was inhibited by tranilast in a dose-dependent manner, showing a significant difference at a concentration of 25 microgram/ml (p<0.05). In colony formation, tranilast reduced the number of colonies at a concentration of 25 microgram/ml (p<0.01). DNA synthesis for 12 hours was attenuated dose-dependently and a significant difference was observed at concentrations of greater than 50 microgram/ml (p<0.05). From cell cycle analysis, a dose-dependent increase in the distribution of G0-G1 phase was observed. In the dorsal air sac model, the mean angiogenesis indices in PGHAM-1 chambers were 4.17 +/- 0.22 (control group) and 2.33 +/- 0.84 (treatment group), and in VEGF chambers they were 3.60 +/- 0.67 (control group) and 1.92 +/- 0.42 (treatment group), In the peritoneal dissemination model, the quantity of sanguineous ascites, the number and the size of diaphragmatic nodules and the microvessel density (MVD) of the metastatic site were reduced by tranilast significantly. In conclusion, the anti-tumor effect of tranilast on proliferation and on tumor-angiogenesis was confirmed in experimental pancreatic cancer.
PMID: 12068313 [PubMed - indexed for MEDLINE

Rich66 06-15-2009 08:39 AM

<dl class="AbstractPlusReport"><dt class="head">1: Prostate. 2009 May 11. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...nce_150x34.gif <script language="JavaScript1.2"><!-- var Menu19434660 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1943 4660&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor beta1-associated osteoblastic changes.

<!--AuthorList-->Izumi K, Mizokami A, Li YQ, Narimoto K, Sugimoto K, Kadono Y, Kitagawa Y, Konaka H, Koh E, Keller ET, Namiki M.
Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
BACKGROUND: Tranilast is a therapeutic agent used in treatment of allergic diseases, although it has been reported to show anti-tumor effects on some cancer cells. To elucidate the effects of tranilast on prostate cancer, we investigated the mechanisms of its anti-tumor effect on prostate cancer. METHODS: The anti-tumor effects and related mechanisms of tranilast were investigated both in vitro on prostate cancer cell lines and bone-derived stromal cells, and in vivo on severe combined immunodeficient (SCID) mice. We verified its clinical effect in patients with advanced hormone refractory prostate cancer (HRPC). RESULTS: Tranilast inhibited the proliferation of LNCaP, LNCaP-SF, and PC-3 cells in a dose-dependent manner and growth of the tumor formed by inoculation of LNCaP-SF in the dorsal subcutis and in the tibia of castrated SCID mice. Flow cytometry and TUNEL assay revealed induction of cell cycle arrest and apoptosis by tranilast. Tranilast increased expression of proteins involved in induction of cell cycle arrest and apoptosis. Coculture with bone-derived stromal cells induced proliferation of LNCaP-SF cells. Tranilast also suppressed secretion of transforming growth factor beta1 (TGF-beta1) from bone-derived stromal cells, which induced their differentiation. Moreover, tranilast inhibited TGF-beta1-mediated differentiation of bone-derived stromal cells and LNCaP-SF cell migration induced by osteopontin. In the clinical investigation, PSA progression was inhibited in 4 of 16 patients with advanced HRPC. CONCLUSIONS: These observations suggest that tranilast may be a useful therapeutic agent for treatment of HRPC via the direct inhibitory effect on cancer cells and suppression of TGF-beta1-associated osteoblastic changes in bone metastasis. Prostate (c) 2009 Wiley-Liss, Inc.
PMID: 19434660 [

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