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.

Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis

“…Obesity per se has also been shown to increase intestinal proliferation (Mao et al 2013), and data from our lab and others have shown that HFD can exacerbate tumorigenesis in several Apc models (Day et al 2013; Gravaghi et al 2008; Hata et al 2011; Huffman et al 2013; Pettan-Brewer et al 2011), including Apc -deficient Lgr5+-ISCs (Beyaz et al 2016). However, even when combined with obesity, Pten deficiency per se in Lgr5-ISCs, in the absence of Apc mutations, is insufficient to drive adenoma formation in these mice, even up to 15 mo of age.…”

“…Obesity and diet are also strong regulators of CRC risk and progression in humans (Bardou, et al 2013; Cheskin and Prosser 2007; Giovannucci and Michaud 2007; Kim, et al 2006; Pischon, et al 2006; Schlesinger, et al 2015), and intestinal tumor development in rodent models (Beyaz, et al 2016; Day, et al 2013; Gravaghi, et al 2008; Hata, et al 2011; Huffman, et al 2013; Pettan-Brewer, et al 2011). Even prior to tumor initiation, obesity appears to ‘prime’ the normal intestinal epithelium toward tumor development, by promoting proliferation of ISCs and hypertrophy of the epithelium (Mao, et al 2013), while also altering the epigenomic landscape of the colonic epithelium in a manner resembling cancer progression (Li, et al 2014).…”

“…More recently, diet-induced obesity was found to increase the number and function of Lgr5+ ISCs, while also promoting stemness and tumorigenicity of progenitor cells after inactivation of Apc (Beyaz et al 2016). Although obesity can clearly instigate processes related to increase tumor risk, as well as accelerate intestinal tumorigenesis following loss of Apc in ISCs and epithelium (Beyaz et al 2016; Day et al 2013; Gravaghi et al 2008; Hata et al 2011; Huffman et al 2013; Pettan-Brewer et al 2011), whether obesity can promote Lgr5+-ISC-derived tumorigenesis via non-canonical mechanisms involving PI3K signaling (Huang and Chen 2009; Vucenik and Stains 2012), has not been investigated. Here we demonstrate that while obesity can modify the transcriptome of Lgr5+-ISCs and expression of specific metabolic pathways, it fails to alter genes related to the Akt signaling and other proliferative pathways in Lgr5+-ISCs.…”

The regulation of FGF21 gene expression by metabolic factors and nutrients

“…Curcumin has a variety of pharmacologic properties. It has been demonstrated to have systemic anti-inflammatory activity and beneficial effects in several types of cancers both in animals and humans [112][113][114][115][116][117], and in individuals with dermatitis [118], Crohn's disease [119], and ulcerative colitis [120]. In addition, curcumin has been shown to improve metabolic disorders associated with hyperlipidemia and hyperglycemia [121][122][123][124][125].…”

Curcumin ameliorates the tumor-enhancing effects of a high-protein diet in an azoxymethane-induced mouse model of colon carcinogenesis

“…In fact, curcumin was found to be one of the most effective chemopreventive agents against CRC [31]. Recent reports on the antitumor effect of curcumin in APC Min mice fed a high-fat diet [32] and in db/db obese mice [33] suggest that curcumin might also be effective in the prevention of obesity-associated colon cancer.…”