1-methylpropyl-2-imidazolyl-disulfide and Neoplasm-Metastasis

Thioredoxin-1 (Trx-1) is a small redox protein, which plays an important role in many biological processes. Although increased expression of Trx-1 in various solid tumors has been reported, the prognostic significance and function of Trx-1 in human gastric cancer (GC) are still unclear. Here, we investigated the clinical and prognostic significance of Trx-1 expression and the function and mechanism of Trx-1 in human GC.. We analyzed Trx-1 mRNA expression from the GEO database and Trx-1 protein expression in 144 GC tissues using immunohistochemistry. Effects of Trx-1 on GC cell were assessed. Increased Trx-1 expression was found in GC tissues and associated with poor prognosis and aggressive clinicopathological characteristics in patients with GC. High Trx-1 expression predicted poor prognosis, and its expression was an independent prognostic factor for overall survival of GC patients. Knockdown of Trx-1 expression inhibited GC cell growth, migration, and invasion. Our results indicate that Trx-1 may be a promising prognostic indicator and therapeutic target for GC patients.

Topics: Aged; Animals; Apoptosis; Cell Movement; Cell Proliferation; Disease Progression; Disulfides; Female; Humans; Imidazoles; Lentivirus; Male; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Stomach Neoplasms; Thioredoxins; Up-Regulation

1-Methylpropyl 2-imidazolyl disulfide (PX-12) has been proposed as an inhibitor of thioredoxin-1 (Trx-1) with antitumor activity. However, the antitumor activity of the Trx-1 redox signaling inhibitor PX-12 on colorectal cancer is still obscure. In the present study, we showed that PX-12 inhibited the growth of colorectal cancer DLD-1 and SW620 cells in a dose- and time-dependent manner. Further analysis demonstrated that PX-12 reduced cell colony formation and induced a G2/M phase arrest of the cell cycle. In addition, PX-12 treatment induced apoptosis, as observed by the increased number of Annexin V-positive cells and increased activation of caspase-3. Notably, a low dose of PX-12 inhibited colorectal cancer cell migration and invasion. Treatment of cancer cells with PX-12 reduced NOX1, CDH17 and S100A4 mRNA expression, and increased KLF17 mRNA expression. Moreover, PX-12 decreased S100A4 protein expression in the colorectal cancer cells. Collectively, the present study demonstrates the antitumor effects and therapeutic potential of PX-12 in colorectal cancer.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Disulfides; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Neoplasm Invasiveness; Neoplasm Metastasis; Oxidation-Reduction; RNA, Messenger; Signal Transduction; Thioredoxins