tranilast and Prostatic-Neoplasms

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

In bone metastatic sites, prostate cancer cells proliferate on interacting with osteoclasts. Tranilast, which is used for an antiallergic drug, has been shown to inhibit growth of several cancers and stromal cells. The present study was conducted to assess suppressive effects of Tranilast on prostate cancer growth and osteoclast differentiation in vivo and in vitro.. In vivo, rat prostate cancer tissue was transplanted onto cranial bones of F344 rats and Tranilast was given for 9 days at doses of 0, 200, or 400 mg/kg/day. In vitro, human prostate cancer cell lines, LNCaP, PC3, and DU145, the rat prostate cancer cell line, PLS-10, and rat bone marrow cells were similarly treated with the agent.. In vivo, tumor volumes were significantly decreased in the high dose group. While cell proliferation did not appear to be affected, apoptosis was induced and tumor necrosis was apparent. Cranial bone defects were decreased in the high dose group. In vitro, cell proliferation rates of all four cell lines were reduced by Tranilast and increased apoptosis was observed in LNCaP and PLS-10. In addition, Tranilast significantly reduced osteoclast differentiation of rat bone marrow cells. Western blot analysis of PLS-10 and LNCaP revealed that phospho-GSK3beta was up-regulated and phospho-Akt was down-regulated.. Tranilast here suppressed rat prostate cancer growth and osteoclast differentiation. Growth of human prostate cancer cells was also inhibited. Thus, this agent deserves consideration as a candidate for conventional therapy of bone metastatic prostate cancer.

Topics: Animals; Apoptosis; Blotting, Western; Bone Marrow Cells; Bone Neoplasms; Cell Differentiation; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Male; Necrosis; Neoplasm Invasiveness; Neoplasm Transplantation; ortho-Aminobenzoates; Osteoclasts; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred F344; Skull; Up-Regulation

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