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.
Keywords: CC; IFC-305; Intestinal toxicity; Methylation; PPAR-r; Radiotherapy.
Copyright © 2019. Published by Elsevier Masson SAS.