tranilast and Adenocarcinoma

Tranilast is a therapeutic agent used in treatment of allergic diseases. It has been reported previously that tranilast has antitumour effects on prostate cancer cells. This study examined whether tranilast has clinical benefit for prostate cancer patients.. Twenty-one Japanese patients with advanced castration-resistant prostate cancer (CRPC) were administered tranilast orally.. All patients had already been treated with combined androgen blockade followed by one or more salvage therapies and their prostate-specific antigen (PSA) continued to increase before starting tranilast. Median follow-up time was 14 months and median tranilast treatment time was 5 months. PSA progression was inhibited in 5 CRPC patients with bone metastasis. The survival rates at 12 and 24 months were 74.5% and 61.5%, respectively.. Although this study involved only pilot data, it indicates that tranilast may improve the prognosis of patients with advanced CRPC.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Orchiectomy; ortho-Aminobenzoates; Prostate-Specific Antigen; Prostatic Neoplasms

The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC).. Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett's EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis.. Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors.. Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Esophageal Neoplasms; Furosemide; Humans; Neoplastic Stem Cells; Solute Carrier Family 12, Member 2; TRPV Cation Channels

Scirrhous gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g., ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and cancer-associated fibroblasts are the suggested cause of the disease. We elucidated the mechanisms of tumor growth and fibrosis using human peritoneal mesothelial cells (HPMCs) and investigated the effects of tranilast treatment on cells and a xenograft mouse model of fibrosis.. HPMCs were isolated from surgically excised omentum and their interaction with MKN-45 gastric cancer cells was investigated using co-culture. Furthermore, a fibrosis tumor model was developed based on subcutaneous transplantation of co-cultured cells into the dorsal side of nude mice to form large fibrotic tumors. Mice were subsequently treated with or without tranilast.. The morphology of HPMCs treated with transforming growth factor (TGF)-β1 changed from cobblestone to spindle-type. Moreover, E-cadherin was weakly expressed whereas high levels of α-smooth muscle actin expression were observed. TGF-β-mediated epithelial-mesenchymal transition-like changes in HPMCs were inhibited in a dose-dependent manner following tranilast treatment through inhibition of Smad2 phosphorylation. In the mouse model, tumor size decreased significantly and fibrosis was inhibited in the tranilast treatment group compared with that in the control group.. Tranilast acts on the TGF-β/Smad pathway to inhibit interactions between cancer cells and cancer-associated fibroblasts, thereby inhibiting tumor growth and fibrosis. This study supports the hypothesis that tranilast represents a novel strategy to prevent fibrous tumor establishment represented by peritoneal dissemination.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Disease Progression; Epithelial-Mesenchymal Transition; Fibroblasts; Fibrosis; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Omentum; ortho-Aminobenzoates; Stomach Neoplasms; Xenograft Model Antitumor Assays

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.. 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).. 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.. 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.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Animals; Anti-Allergic Agents; Apoptosis; Bone Neoplasms; Castration; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, SCID; Middle Aged; ortho-Aminobenzoates; Osteoblasts; Osteosarcoma; Prostate-Specific Antigen; Prostatic Neoplasms; Transforming Growth Factor beta1

Extensive infiltration of normal brain tissue and suppression of anti-tumor immune surveillance mediated by molecules such as transforming growth factor-beta (TGF-beta) are key biological features that contribute to the malignant phenotype of human gliomas. Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) is an anti-allergic compound used clinically to control atopic and fibrotic disorders. These effects are attributed to the suppression of TGF-beta1 synthesis and interference with growth factor-mediated proliferation and migration of fibroblasts and vascular smooth muscle cells. Here, we show that tranilast inhibits DNA synthesis and proliferation of human malignant glioma cells and promotes p21 accumulation in the absence of cytotoxicity. Further, tranilast reduces the release of TGF-beta1 and TGF-beta2 by glioma cells and inhibits migration, chemotactic responses and invasiveness. These effects are not associated with a reduction of alpha(v)beta(3) integrin expression at the cell surface but appear to involve inhibition of matrix metalloproteinase-2 expression and activity. Neither the tranilast-mediated inhibition of proliferation nor the inhibition of migration was counteracted by supplementation with exogenous TGF-beta. Finally, tranilast administered orally inhibited the growth of experimental 9L rat gliomas and reduced expression of TGF-beta2 in vivo. We conclude that tranilast might be a useful therapeutic agent for the treatment of human malignant glioma because of a TGF-beta-independent abrogation of the malignant phenotype of proliferation, migration and invasiveness and because of the antagonism of TGF-beta-associated immunosuppression.

Topics: 3T3 Cells; Adenocarcinoma; Animals; Brain Neoplasms; Cell Division; Chemotaxis; Female; Glioma; Histamine H1 Antagonists; Humans; Kinetics; Matrix Metalloproteinase 2; Mice; Neoplasm Invasiveness; Neuroblastoma; ortho-Aminobenzoates; Ovarian Neoplasms; Platelet Aggregation Inhibitors; Receptors, Vitronectin; Transforming Growth Factor beta; Tumor Cells, Cultured