tranilast and Neoplasm-Metastasis

Transforming growth factor β1 (TGF-β1) is an important epithelial-mesenchymal transition (EMT) activator that regulates the expression of E-cadherin and vimentin through Smad signalling. Tranilast is an anti-allergic drug that inhibits TGF-β1, and is used in the treatment of keloids and hypertrophic scars. We investigated whether tranilast inhibits TGF-β1-induced EMT and invasiveness in human non-small cell lung cancer cell lines.. We examined the effects of tranilast treatment on EMT markers, TGF-β1/Smad signalling, and cell invasiveness in A549 and PC14 cells. Tumours from a mouse orthotopic lung cancer model with or without tranilast treatment were also immunohistochemically evaluated.. Tranilast increased E-cadherin expression via Smad4 suppression and inhibited cell invasion in TGF-β1-stimulated cells. Tranilast treatment of the in vivo mouse model reduced the pleural dissemination of cancer cells and suppressed vimentin and Smad4 expression.. Tranilast inhibited TGF-β1-induced EMT and cellular invasion/metastasis by suppressing Smad4 expression in cancer cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; ortho-Aminobenzoates; Smad4 Protein; Transforming Growth Factor beta1

Abnormal expression of stromal cells and extracellular matrix in tumor stroma creates a tight barrier, leading to insufficient extravasation and penetration of therapeutic agents. Cancer-associated fibroblasts (CAFs) take on pivotal roles encouraging tumor progression.. To surmount the refractoriness of stroma, we constructed a multi-targeting combined scenario of anti-CAFs agent tranilast and antitumor agent docetaxel micelles (DTX-Ms). Tranilast cut down crosstalk between tumor cells and stromal cells, ameliorated the tumor microenvironment, and enhanced the antiproliferation efficacy of DTX-Ms on cancer cells.. Diverse experiments demonstrated that tranilast enhanced DTX-Ms' antitumor effect in a two-stage pattern by CAFs ablation, tumor cell migration blocking, and metastasis inhibition. Along with activated CAFs decreasing in vivo, the two-stage therapy succeeded in reducing interstitial fluid pressure, normalizing microvessels, improving micelles penetration and retention, and inhibiting tumor growth and metastasis. Interestingly, tranilast alone failed to inhibit tumor growth in vivo, and it could only be used as an adjuvant medicine together with an antitumor agent.. Our proposed two-stage therapy offers a promising strategy to enhance antitumor effects by breaking down CAFs barrier and increasing micellar delivery efficiency.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Movement; Cell Proliferation; Docetaxel; Extracellular Fluid; Female; Humans; Mice; Mice, Inbred BALB C; Micelles; Microvessels; Neoplasm Metastasis; Neoplasms; Organ Specificity; ortho-Aminobenzoates; Spheroids, Cellular; Taxoids; Tissue Distribution; Tumor Microenvironment