ABSTRACT
AIMS: Alpinia katsumadai was recently found in our previous study to have anti-migratory and anti-invasion activities against HT-1080 cells. However, the study did not demonstrate the exact component of Alpinia katsumadai with anti-migratory and anti-invasive activities. We tested the effects and relevant mechanism of cardamonin (CDN) on the migration and invasion of cancer cells. MAIN METHODS: Migration and invasion of cancer cells were measured using multi-well chambers. Zymography and Western blots were used to examine the effects of CDN on the activities of matrix metalloproteinases (MMPs) and expression of transglutaminase-2 (Tgase-2). KEY FINDINGS: CDN, but not alpinetin, dose-dependently suppressed the migration and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced invasion of HT-1080 sarcoma cells. CDN suppressed the expression of Tgase-2, MMP-2, NF-κB and MMP-9 in HT-1080 cells, and suppressed MMP-2 and MMP-9 activities. Gene silencing of Tgase-2 suppressed the migration and invasion of HT-1080 cells and suppressed the activities of MMP-2 and MMP-9. Migration of various cancer cells having high levels of Tgase-2 were also inhibited by CDN. CDN and Alpinia katsumadai extracts also directly inhibited the activity of Tgase-2. SIGNIFICANCE: CDN inhibits migration of several cancer cell lines expressing Tgase-2 via suppression of Tgase-2 expression and inhibition of Tgase-2 activity. The finding that CDN has Tgase-2 inhibitory activity will give us a new scaffold or clue of pharmacophore for the development of more effective Tgase-2 inhibitors.
Subject(s)
Cell Movement/drug effects , Chalcones/pharmacology , GTP-Binding Proteins/drug effects , Neoplasm Invasiveness/physiopathology , Transglutaminases/drug effects , Cell Line, Tumor , Cell Migration Assays , Cell Movement/physiology , Dose-Response Relationship, Drug , GTP-Binding Proteins/biosynthesis , GTP-Binding Proteins/physiology , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/physiology , Gene Silencing/drug effects , Gene Silencing/physiology , Humans , Matrix Metalloproteinase 2/biosynthesis , Matrix Metalloproteinase 2/drug effects , Matrix Metalloproteinase 2/physiology , Matrix Metalloproteinase 9/biosynthesis , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/physiology , NF-kappa B/biosynthesis , NF-kappa B/drug effects , NF-kappa B/physiology , Neoplasm Invasiveness/prevention & control , Protein Glutamine gamma Glutamyltransferase 2 , Transglutaminases/biosynthesis , Transglutaminases/physiologyABSTRACT
PURPOSE: This retrospective study was carried out to evaluate the efficacy and toxicity of radiation therapy (RT) with/without cisplatin-based chemotherapy in nasopharyngeal cancer (NPC). MATERIALS AND METHODS: One hundred forty six patients with NPC received curative RT and/or cisplatin-based chemotherapy. Thirty-nine patients were treated with induction chemotherapy (IC), including cisplatin and 5-fluorouracil followed by RT. Another 63 patients were treated with concurrent chemoradiotherapy (CCRT) using cisplatin, and 22 patients were treated with IC followed by CCRT. The remaining 22 patients were treated with RT alone. RESULTS: One hundred four (80.0%) patients achieved complete response (CR), and 23 (17.7%) patients achieved partial response (PR). The patterns of failure were: locoregional recurrences in 21.2% and distant metastases in 17.1%. Five-year overall survival (OS) and progression free survival (PFS) were 50.7% and 45.0%, respectively. Multivariate Cox stepwise regression analysis revealed CR to chemoradiotherapy to be a powerful prognostic factor for OS. CR to chemoradiotherapy and completion of radiation according to the time schedule were favorable prognostic factors for PFS. A comparison of each treatment group (IC --> RT vs. CCRT vs. IC --> CCRT vs. RT alone) revealed no significant differences in the OS or PFS. However, subgroup analysis showed significant differences in both OS and DFS in favor of the combined chemoradiotherapy group compared with RT alone, for stage IV and T3-4 tumors. Grade 3-4 toxicities were more common in the combined chemoradiotherapy arm, particularly in the CCRT group. CONCLUSIONS: This study was limited in that it was a retrospective study, much time was required to collect patients, and there were imbalances in the number of patients in each treatment group. Combined chemoradiotherapy remarkably prolonged the OS and PFS in subgroup patients with stage IV or T3-4 NPC.
