Curcumin suppresses intestinal polyps in APC Min mice fed a high fat diet

Abstract

Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Various risk factors have been associated with CRC including increasing age and diet. Epidemiological and experimental studies have implicated a diet high in fat as an important risk factor for colon cancer. High fat diets can promote obesity resulting in insulin resistance and inflammation and the development of oxidative stress, increased cell proliferation, and suppression of apoptosis. Because of the high consumption of dietary fats, especially saturated fats, by Western countries, it is of interest to see if non-nutrient food factors might be effective in preventing or delaying CRC in the presence of high saturated fat intake. Curcumin (Curcuma longa), the main yellow pigment in turmeric, was selected to test because of its reported anti-tumor activity. APC Min mice, which develop intestinal polyps and have many molecular features of CRC, were fed a diet containing 35% pork fat, 33% sucrose, and a protein and vitamin mineral mixture (HFD) with or without 0.5% curcumin. These cohorts were compared to APC Min mice receiving standard rodent chow (RC) with 8% fat. APC Min mice fed the HFD for 3 months had a 23% increase in total number of polyps compared to APC Min mice on RC. Curcumin was able to significantly reverse the accelerated polyp development associated with the HFD suggesting it may be effective clinically in helping prevent colon cancer even when ingesting high amounts of fatty foods. The anti-tumor effect of curcumin was shown to be associated with enhanced apoptosis and increased efficiency of DNA repair. Since curcumin prevented the gain in body weight seen in APC Min mice ingesting the HFD, modulation of energy metabolism may also be a factor.

Keywords: DNA damage; apoptosis; colon cancer; curcumin; high fat diet; oxidative stress.

Fig. 1

The number of small-sized polyps (up to 3 mm in diameter) in the small intestine of APC Min mice fed a high fat (HF) diet is increased compared to the number of polyps in mice fed chow (*p≤0.05). When curcumin (C) is added to the HF diet, small-sized polyp numbers are attenuated compared to polyp numbers in mice ingesting HF diet without curcumin (*p≤0.05). N=15–18 mice for each of the three cohorts.

Fig. 2

Apoptosis, as assessed immunohistochemically by apoptotic index, is increased in intestinal polyps from APC Min mice ingesting high fat (HF) diet with curcumin (C), but not in polyps from APC Min mice ingesting HF diet without curcumin or regular rodent chow diet (*p≤0.05). N=15–18 mice for each of the cohorts.

Fig. 3

Oxidation-induced DNA damage, as assessed immunohistochemically by 8-oxoG index, in intestinal polyps from APC Min mice is not affected by ingestion of a high fat (HF) diet with or without curcumin. However, ingestion of the HF diet appears to attenuate oxidation-induced DNA damage observed in non-polyp tissue from APC Min mice ingesting regular rodent chow (*p≤0.05). N=15–18 mice for each of the cohorts.

Fig. 4

DNA repair activity, as assessed immunohistochemically by XRCC1 expression index, is increased in intestinal polyps from APC Min mice fed high fat (HF) diet with curcumin (C) compared to APC Min mice ingesting HF diet without curcumin or regular rodent chow (*p≤0.05). Interestingly, the XRCC1 expression index is decreased in intestinal non-polyp tissue from APC Min mice ingesting HF diet with or without curcumin compared to APC Min mice ingesting regular rodent chow (*p≤0.05). N=15–18 mice for each of the cohorts.

Fig. 5

Body weights of APC Min mice fed a diet high in fat and calories with curcumin added (HFHC+C) or without curcumin (HFHC) or fed regular rodent chow (RC). Starting at week 4, body weight is significantly lower in APC Min mice ingesting the high fat diet containing curcumin (N=32) compared to APC Min mice ingesting the high fat diet without curcumin (N=32; p<0.01) and is comparable to body weight of APC Min mice ingesting regular rodent chow.