Abstract
Colorectal adenocarcinoma is the most common type of gastrointestinal cancer. Colon adenocarcinoma is a major health problem worldwide due to the high prevalence and mortality rates associated with the disease. The majority of colorectal carcinomas are adenocarcinomas, which originate from the epithelial cells of the colorectal mucosa. HT-29 cells, which originate from human colon adenocarcinoma, are used as an in vitro model to investigate the effect of malignant transformation on the expression of cellular constituents and functions of the intestinal epithelium. Nitric oxide (NO) is a signaling molecule, which is involved in inflammation and carcinogenesis. It has been reported that enhanced inducible NO synthase (iNOS) activity and the resulting NO concentrations in human colon carcinoma contribute to tumor progression and vascular invasion. The present study investigates the effect of pro-inflammatory cytokine-induced nitric oxide (NO) production and iNOS expression on the invasion of human colorectal adenocarcinoma HT-29 cells, and the effect of extract from Cnidii Rhizoma on NO production and the invasiveness of HT-29 cells. Treatment of HT-29 cells with cytokines, 100 U/ml interferon γ, 10 ng/ml interleukin-1 α and 25 ng/ml tumor necrosis factor α was found to increase NO production. Pretreatment of the cells with Cnidii Rhizoma (0.1–5 mg/ml) resulted in an inhibition of cytokine-induced NO production and iNOS expression. The invasiveness of HT-29 cells through Matrigel was significantly increased by treatment with cytokines. Cnidii Rhizoma inhibited the invasiveness of cytokine-treated HT-29 cells through the Matrigel-coated membrane in a concentration-dependent manner. Matrix metalloproteinase (MMP) activity in HT-29 cells increased following the treatment with cytokines, and pretreatment of the cells with Cnidii Rhizoma inhibited cytokine-induced MMP-2 activity. These results provide sufficient information for the further development of Cnidii Rhizoma as an antitumor metastatic agent for the treatment of colon cancer.
Highlights
Nitric oxide (NO) is an important bioactive signaling molecule that is significant in numerous physiological processes in the cardiovascular, neurological and immune systems
The formation of NO from arginine is catalyzed by three types of NO synthase (NOS): Endothelial NOS, neuronal NOS and the inducible isoenzyme (2). inducible NO synthase (iNOS) expression is generally induced by inflammatory stimuli and is responsible for the production of large quantities of NO
Matrix metalloproteinases (MMPs) production appears to be a marker for cancer cells with elevated metastatic potential (7) and the activation of MMP activity has been detected in colon carcinoma (8)
Summary
Nitric oxide (NO) is an important bioactive signaling molecule that is significant in numerous physiological processes in the cardiovascular, neurological and immune systems. MMP production appears to be a marker for cancer cells with elevated metastatic potential (7) and the activation of MMP activity has been detected in colon carcinoma (8). Colorectal cancer is the second most common cause of cancer in women (9.2% of diagnoses) and the third most common in men (10.0%) worldwide (15) It is a multifactorial disease etiology, which includes genetic factors, environmental exposures, such as diet, and inflammatory conditions of the digestive tract. The present study investigates the ability of pro‐inflammatory cytokine‐induced NO to modulate the invasiveness of human colorectal adenocarcinoma HT‐29 cells, which is a cell line mainly used as an in vitro colon epithelial cell model to investigate absorption, transport and secretion by intestinal cells, and the effect of the extract from Cnidii Rhizoma on NO production and invasiveness of HT‐29 cells
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