Evaluation of chemopreventive potential of xanthone from Swertia chirata against DMBA/croton oil-induced chemical carcinogenesis in Swiss mice

The present study was designed to determine the chemo­preventive efficiency of 1,5,8-trihydroxy-3-methoxy xanthone, abbreviated as TMX, isolated and purified from the aerial part of the plant Swertia chirata against 9,10-dimethylbenz[a]-anthracene (DMBA)/croton oil-induced skin cancer, and probe into the molecular mechanism. All the mice in the carcinogen control group developed severe dysplastic lesions after the 14th week of application of the carcinogen, which pro­gressed to carcinoma in situ around the 20th week; this was validated histologically. However, after TMX treatment, only around 50% of mice developed papilloma which histologically was found to be restrictive to moderate to severe hyperplastic change in the 14th and 20th week. The chemopreventive potential was determined by calculating the attributable risk (AR), which was –11.3 for the 14th week and increased up to –17.5 for the 20th week. To ascertain the effect of TMX treatment on inflammation, the effect of TMX on inflammatory cytokines was studied by ELISA. It revealed a significant reduction in inflammation upon TMX treatment for the 20th week. As TMX could hold its chemopreventive potential up to the 20th week, the molecular mechanism of restriction was studied for the 20th week of treatment. Skin forms a rich source of stem cells which orchestrate the progression of carcinogenesis and become cancer stem cells (CSCs). β-Catenin and KRAS are known central modulators of CSCs, that play a crucial role in the progression of skin carcinogenesis. We observed that TMX treatment inhibited KRAS and nuclear translocation of β-catenin causing its cytoplasmic degradation by P-53 and P-21-mediated pathway, thereby exerting its chemopreventive potential.