Tranilast inhibits the growth and metastasis of mammary carcinoma

• Published in: Anti-cancer drugs Vol. 20; no. 5; p. 334
• Main Authors: Chakrabarti, Rabindranath, Subramaniam, Venkateswaran, Abdalla, Salma, Jothy, Serge, Prud'homme, Gérald J
• Format: Journal Article
• Language: English
• Published: England 01.06.2009
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Carcinoma - drug therapy; Carcinoma - pathology; Carcinoma - prevention & control; Carcinoma - secondary; Cell Line, Tumor - drug effects; Cell Line, Tumor - transplantation; Cell Transdifferentiation - drug effects; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Female; Humans; Liver Neoplasms - prevention & control; Liver Neoplasms - secondary; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lymphoma - pathology; Mammary Neoplasms, Experimental - drug therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Neoplasm Proteins - antagonists & inhibitors; Organ Specificity; ortho-Aminobenzoates - therapeutic use; Rats; Rats, Sprague-Dawley; Smad2 Protein - metabolism; Species Specificity; Thymoma - pathology; Thymus Neoplasms - pathology; Transforming Growth Factor beta - antagonists & inhibitors
• ISSN: 1473-5741
• DOI: 10.1097/CAD.0b013e328327994e

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.