CHEMOPROTECTIVE ROLE OF 6-GINGEROL IN ULCERATIVE COLITIS AND COLORECTAL CANCER IN BALB/c MICE

Abstract

Ulcerative colitis (UC) is an inflammatory disease of the colon that predisposes to colorectal cancer (CRC), the fourth leading cause of cancer death worldwide. Some drugs used in treatment of UC and CRC have adverse effects. Therefore, the search for new drug candidates is desirable. A bioactive component, 6-Gingerol (6-G) from ginger rhizome, has been reported to possess anti-inflammatory activity. However, there is paucity of information regarding the effect of 6-G in UC and CRC. This study was designed to evaluate the chemoprotective role of 6-G in UC and CRC in mice. Male BALB/c mice (n=138, 18.0±1.0 g) were orally treated in three different experimental models. Acute UC model consisted of 6 groups (n=7) of mice orally treated with corn oil (control), 6-G (100 mg/kg), dextran sulfate sodium (DSS) (5% w/v), DSS+6-G (50 mg/kg), DSS+6-G (100 mg/kg) and DSS+6-G (200 mg/kg). The DSS and 6-G were administered for 7 and 14 days, respectively. Chronic UC model consisted of 6 groups (n=6) of mice orally treated with corn oil, 6-G (100 mg/kg), sulfasalazine (100 mg/kg), DSS (2.5%,w/v), DSS+6-G (100 mg/kg) and DSS+sulfasalazine (100 mg/kg). The sulfasalazine, DSS and 6-G were administered for 63, 21 and 63 days, respectively. The CRC model consisted of 4 groups (n-15) of mice orally treated with corn oil, 6-G (100 mg/kg), Benzo[a]pyrene (125 mg/kg)+DSS (4% w/v) [BDS] and BDS+6-G (100 mg/kg). The BDS and 6-G were administered for 28 and 119 days, respectively. Mice were sacrificed in the models and samples (blood and colon) collected. Colon myeloperoxidase activity was determined spectrophotometrically. Plasma tumour necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) were assessed using ELISA. Disease activity index (DAI) and tumour incidence (TI) were scored using standard methods. Adenocarcinoma was detected by microscopy. Cyclooxygenase-2, β-catenin, cyclin D1 (CCNDI), adenomatous polyposis coli (APC) and p53 expression were assessed using immunohistochemistry, while apoptosis was detected using TUNEL assay. Data were analysed using ANOVA at α0.05. In acute UC model, DSS significantly increased DAI (5.7±0.6), myeloperoxidase (2.8±0.3 unit/mg protein), TNF-α (32.1±2.1 pg/ml), IL-1β (111.4±4.2 pg/ml) relative to control (0.0±0.0, 1.5±0.1 unit/mg protein 19.2±1.9, 90.2±3.9 pg/ml), respectively. The 6-G (50, 100 and 200 mg/kg) significantly decreased DAI (1.3±0.1, 1.0±0.1, 1.1 ±0.2), myetoperoxidase (2.1±0.6, 1.7±0.2, 1.9±0.4 unit/mgprotein), TNF-α (18.1±1.1, 19.5±3.0, 24.0±2.3 pg/mL) and IL-1β (93.3±2.8, 91.5±4.8, 90.0±3.7 pg/ml). In chronic UC model, DSS significantly increased mycloperoxidase (5.2±0.3 unit/mg protein), β-catenin (91.9±6.0%) and cyclooxygenase-2 expression (81.0±1.5%) relative to control (1.8±0.2 unit/mg protein, 13.3±3.4, 7.5±0.5% respectively. Sulfasalazine and 6-G attenuated myeloperoxidase (50.0 and 42.3%), β-catenin (53.3 and 40.0%) and cyclooxygenase-2 (33.8 and 34.0%). In CRC model, BDS induced adenocarcinoma with 78.0, 69.4 and 86.6% decrease in APC, p53 expression and number of apoptotic cells, respectively. while TI, β-catenin and CCNDI expressions were increased (97.0%, 68.4% and 89.2%, respectively). The 6-G increased APC, p53 expression and number of apoptotic cells by 71.8, 69.0 and 75.0%, respectively but reduced TI,β-catenin and CCND1 expression by 41.5. 21.0 and 41.6%, respectively. The 6-Gingerol elicited chemoprotective effect in ulcerative colitis and colorectal cancer via anti-inflammatory and anti-tumourigenic properties.