Nobiletin and atorvastatin synergistically inhibit azoxymethane (AOM)‐induced colon carcinogenesis in rats

Abstract

Accumulating studies have suggested that combination of cancer chemopreventive agents may produce enhanced protective effects against carcinogenesis than each individual agent alone. The enhanced efficacy by the combination can also lower the required dose for each single agent in the combination, which may lower unwanted side‐effects possibly caused by the use of high dose of individual agents. Herein, we investigated the combination of nobiletin (NBT, a citrus polymethoxyflavone) with atorvastatin (ATST, a lipid‐lowering drug) in an AOM‐induced colon carcinogenesis rat model. The results showed that oral administration of NBT or ATST alone significantly decreased colon tumor incidence and multiplicity. However, co‐treatment of NBT and ATST at their half doses produced stronger inhibitory effect on tumor incidence and multiplicity in comparison to those produced by the treatments with individual NBT or ATST. Statistical analysis confirmed that the enhanced chemopreventive effects on colon carcinogenesis by the combination treatment were synergistic. Immunoblotting results showed that co‐treatment of NBT and ATST had much stronger anti‐proliferative and pro‐apoptotic effects in colonic tissue, which was evidenced by lower expression levels of cyclin D/CDK4 and cyclin E/CDK2, and higher levels of cleaved caspase‐7, leaved caspase‐3, cleaved PARP and p53 produced by the combination treatment than the treatments with NBT or ATST alone. In conclusion, our results demonstrated the strong synergy in inhibiting colon carcinogenesis produced by NBT and ATST in combination in vivo, which provided a basis for using NBT and ATST in combination for colon cancer chemoprevention.