Mechanisms of colitis-accelerated colon carcinogenesis and its prevention with the combination of aspirin and curcumin: Transcriptomic analysis using RNA-seq
Chronic inflammation is known to play a significant role in the development of pathogenesis of tumors in multiple human cancers, including colorectal cancer (CRC), the fourth leading cause of cancer-related deaths worldwide. In the US alone, CRC is estimated to account for more than 49,190 deaths in 2016. Colitis-accelerated colon cancer (CAC), a subtype of CRC, is closely associated with inflammatory bowel disease (IBD).
In recent years, though therapeutic options, such as surgery, radiation therapy, chemotherapy, and targeted therapy for CRC treatment have been effective, most of these strategies suffer from various side effects. Aspirin has been found to be an effective agent in lowering the risk of different types of CRC. However, its use has been limited owing to the potential side effects of gastrointestinal bleeding at high-dose. Co-administration of two or more low-dose chemopreventive agents with different molecular mechanisms may be a promising strategy to maximize efficacies and minimize toxicities.
Curcumin, the principal costituent of turmeric, is another widely studied chemopreventive candidate for CRC and has shown promising effects in suppressing inflammation and colon cancer cell growth. Several studies have also demonstrated that both aspirin and curcumin are multi-target chemopreventive agents that modulate various signaling pathways and molecules involved in inflammation, tumor initiation, and tumor progression.
To determine the effect of aspirin, curcumin and their combination in azoxymethane/dextran sulfate sodium
(AOM/DSS) - induced colitis-accelerated colorectal cancer (CAC).
Six-week-old mice were injected with AOM (10 mg/kg) to induce colitis. After a week, the drinking water for the mice injected with AOM was replaced with DSS (1.2% w/v) for 7 days. During DSS administration period, symptoms of acute colitis were monitored by calculating the disease activity index (DAI) daily. Mice were fed with diets supplemented with 0.02% aspirin, 2% curcumin, or 0.01% aspirin + 1% curcumin from 1 week prior to the AOM injection until the experiment was terminated (i.e. 22 weeks after AOM initiation). During the experiment period, body weight and the consumption of food and fluid were recorded every week. At the end of the experiment colons were examined for the tumors as well as used for histological analysis.
- Data suggested that tumor inhibitory efficacy of curcumin was superior to that of aspirin; while their combination at a lower dose produced similar efficacy when compared to that of a higher dose of curcumin at 2%
- RNA-seq analysis showed that low-dose combination of aspirin and curcumin modulated larger gene sets that are known to play important role in the inflammatory network and liver metastasis in CAC
- A small subset of genes were also identified, which may be potential molecular targets of the combination of aspirin and curcumin in preventing CAC
Overall, co-administration of low-dose combination of aspirin and curcumin produced chemopreventive effects against CAC. Furthermore, the transcriptional profile obtained in this study may be helpful in identifying underlying mechanism of the carcinogenesis process of inflammatory CRC as well as the chemopreventive effects and potential molecular targets of aspirin and curcumin.