首页|Effects of hexahydrocurcumin in combination with 5-fluorouracil on dimethylhydrazine-induced colon cancer in rats
Effects of hexahydrocurcumin in combination with 5-fluorouracil on dimethylhydrazine-induced colon cancer in rats
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AIM:To investigate the effects of hexahydrocurcumin (HHC),and its combination with 5-fluorouracil (5-FU)on dimethylhydrazine (DMH)-induced colon cancer in METHODS:Male Wistar rats weighing 100-120 g were used as subject models.Aberrant crypt foci (ACF),early preneoplastic lesions of colon cancer,were induced by subcutaneous injection of DHM (40 mg/kg) twice a week for two weeks.After the first DMH injection,rats were treated daily with vehicle (n =12),curcumin (CUR) (50 mg/kg) (n =12),HHC (50 mg/kg) orally (n =12),and treated weekly with an intraperitoneal injection of 5-FU (50 mg/kg) (n =12),or a combination of 5-FU plus CUR (n =12) and HHC (n =12) at the same dosage(s) for 16 wk.The total number of ACF and large ACF were assessed.Cyclooxygenase (COX)-1 and COX-2 expression were detected by immunohistochemistry in colon tissues.The quantitative data of both COX-1 and COX-2 expression were presented as the percentage of number of positive-stained cells to the total number of cells counted.Apoptotic cells in colon tissues were also visualized using the dUTP-biotin nick end labeling method.Apoptotic index (AI) was determined as the percentage of labeled nuclei with respect to the total number of nuclei counted.RESULTS:The total number of ACF was highest in the DMH-vehicle group (1558.20 ± 17.37),however,the number of ACF was significantly reduced by all treatments,5-FU (1231.20 ± 25.62 vs 1558.20 ± 17.37,P ＜0.001),CUR (1284.20 ± 25.47 vs 1558.20 ± 17.37,P ＜0.001),HHC (1086.80 ± 53.47 vs 1558.20 ± 17.37,P ＜0.001),DMH-5-FU + CUR (880.20 ± 13.67 vs 1558.20± 17.37,P ＜ 0.001) and DMH-S-FU + HHC (665.80 ±16.64 vs 1558.20 ± 17.37,P ＜ 0.001).Interestingly,the total number of ACF in the combined treatment groups,the DMH-5-FU + CUR group (880.20 ± 13.67vs 1231.20 ± 25.62,P ＜ 0.001; 880.20 ± 13.67 vs 1284.20 ± 25.47,P ＜ 0.001) and the DMH-5-FU +HHCgroup (665.80 ± 16.64 vs 1231.20 ± 25.62,P ＜0.001; 665.80 ± 16.64 vs 1086.80 ± 53.47,P ＜ 0.001)were significantly reduced as compared to 5-FU or each treatment alone.Large ACF were also significantly reduced in all treatment groups,5-FU (111.00 ± 7.88 vs 262.20 ± 10.18,P ＜ 0.001),CUR (178.00 ± 7.33 vs 262.20 ± 10.18,P ＜ 0.001),HHC (186.60 ± 21.51 vs 262.20 ± 10.18,P ＜ 0.001),DMH-5-FU + CUR (122.00± 5.94 vs 262.20 ± 10.18,P ＜ 0.001) and DMH-5-FU+ HHC (119.00 ± 17.92 vs 262.20 ± 10.18,P ＜ 0.001)when compared to the vehicle group.Furthermore,in the DMH-5-FU + CUR and DMH-5-FU + HHC groups the formation of large ACF was significantly reduced when compared to CUR (122.00 ± 5.94 vs 178.00 ±7.33,P ＜ 0.005) or HHC treatment alone (119.00 ±17.92 vs 186.60 ± 21.51,P ＜ 0.001),however,this reduction was not statistically different to 5-FU monotherapy (122.00 ± 5.94 vs 111.00 ± 7.88,P =0.217;119.00 ± 17.92 vs 111.00 ± 7.88,P =0.619,respectively).The levels of COX-1 protein after all treatments were not different from normal rats.A marked increase in the expression of COX-2 protein was observed in the DMH-vehicle group.Over-expression of COX-2 was not significantly decreased by 5-FU treatment alone (95.79 ± 1.60 vs 100 ± 0.00,P =0.198).However,over-expression of COX-2 was significantly suppressed by CUR (77.52 ± 1.68 vs 100 ± 0.00,P ＜ 0.001),HHC (71.33 ± 3.01 vs 100 ± 0.00,P ＜ 0.001),5-FU ± CUR (76.25 ± 3.32 vs 100 ± 0.00,P ＜ 0.001) and 5-FU +HHC (68.48 ± 2.24 vs 100 ± 0.00,P ＜ 0.001) in the treated groups compared to the vehicle group.Moreover,CUR (77.52 ± 1.68 vs 95.79 ± 1.60,P ＜ 0.001),HHC (71.33 ± 3.01 vs 95.79 ± 1.60,P ＜ 0.001),5-FU + CUR treatments (76.25 ± 3.32 vs 95.79 ± 1.60,P ＜0.001) and 5-FU + HHC (68.48 ± 2.24 vs 95.79 ± 1.60,P ＜ 0.001) markedly decreased COX-2 protein expression more than 5-FU alone.Furthermore,the AI in all treated groups,5-FU (38.86 ± 4.73 vs 23.56 ± 2.12,P =0.038),CUR (41.78 ± 6.92 vs 23.56 ± 2.12,P ＜0.001),HHC (41.06 ± 4.81 vs 23.56 ± 2.12,P ＜ 0.001),5-FU + CUR (49.05 ± 6.75 vs 23.56 ± 2.12,P ＜ 0.001)and 5-FU + HHC (53.69 ± 8.59 vs 23.56 ± 2.12,P ＜0.001) significantly increased when compared to the DMH-vehicle group.However,the AI in the combination treatments,5-FU + CUR (49.05 ± 6.75 vs 41.78± 6.92,P =0.192; 49.05 ± 6.75 vs 38.86 ± 4.73,P =0.771) and 5-FU + HHC (53.69 ± 8.59 vs 41.06 ± 4.81,P =0.379; 53.69 ± 8.59 vs 38.86 ± 4.73,P =0.245)did not reach significant levels as compared with each treatment alone and 5-FU monotherapy,respectively.CONCLUSION:The combined effects of HHC with 5-FU exhibit a synergistic inhibition by decreasing ACF formation mediated by down-regulation of COX-2 expression.
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