An adenosine derivative (IFC-305) reduced the risk of radiation-induced intestinal toxicity in the treatment of colon cancer by suppressing the methylation of PPAR-r promoter

Abstract Background IFC-305, an adenosine derivative, has been proved to exert a therapeutic effect on radiation-induced intestinal toxicity in colon cancer (CC). The aim of the present study was to investigate the underlying molecular mechanism of protective role of IFC-305 in CC by modifying the methylation of peroxisome proliferator-activated receptor (PPAR)-r promoter. Method Peripheral blood and cancerous tissues samples were collected from the CC patients. Irradiation (IR) mice models were established in comparison with control mice accordingly. Bisulfite sequencing, real-time PCR, Western-blot analysis, immunohistochemistry (IHC) and hematoxylin eosin (HE) staining were performed upon both human and animal samples. Result The results upon the human CC samples demonstrated that the level of methylation of PPAR-r promoter in methylated patients was increased, while the risk of radiation-induced intestinal toxicity in methylated patients was also increased compared with unmethylated patients. Also, the PPAR-r mRNA/protein expression was lower in methylated patients compared with unmethylated patients, thus indicating the presence of PPAR-r promoter methylation repressed PPAR-r expression in vivo. Moreover, in the mice models, IFC-305 treatment partially alleviated radiation-induced toxicity in the columnar epithelia and tubular glands of IR mice, and villus height and the number/circumference of crypts were also increased while the relative number of inflammatory cells was decreased in IR + IFC-305 mice group compared with the control mice. Compared with the control group, the levels of PPAR-r mRNA/protein expression were significantly decreased in IR mice, while the presence of IFC-305 exerted therapeutic effect upon IR rats via elevating the PPAR-r mRNA/protein expression to a certain extent. Conclusion In this study, we demonstrated the relationship between PPAR-r promoter methylation and the risk of radiation-induced intestinal toxicity via studying the clinical samples collected from CC patients. And the study upon mice models suggested that the administration of IFC-305 could alleviate radiation-induced intestinal toxicity through decreasing the methylation of PPAR-r promoter and enhancing the expression of PPAR-r in IR mice.