Evaluation of Punicalagin as a multi‑targeted therapeutic agent against endometrial cancer

Endometrial cancer (EC) has become an increasing clinical concern as the incidence is rising, and treatment options available for advanced disease or recurrent disease are limited. In the present study, the anticancer potential of punicalagin (PCG), a natural ellagitannin polyphenol that comes from pomegranate, was characterized using both in vitro and in vivo models in EC. Two EC cell lines (Ishikawa and SNU‑539) treated with increasing doses of PCG showed dose‑dependent inhibition of cell proliferation and demonstrated a decrease in colony formation. PCG inhibited Transwell migration and an increase in E‑cadherin expression, indicating an inhibition of epithelial‑mesenchymal transition. Further experimental work characterized the mechanisms by which PCG acted and revealed that it decreased the mitochondrial membrane potential and subsequently increased levels of reactive oxygen species, which led to apoptosis as shown by increased BAX expression and Hoechst/PI staining. In addition, PCG showed signs of autophagy, especially in the Ishikawa cells, as indicated by increased levels of LC3‑IIB and the formation of autophagic vacuoles. In vivo studies using a xenograft mouse model showed that treatment with PCG significantly reduced tumor volume and weight, whereas body weight was not significantly affected, thus highlighting strong anticancer efficacy coupled with very low toxicity. Overall, the present study highlights PCG as a promising natural compound with multitarget anticancer activity against EC and warrants further preclinical and clinical research as a potential treatment option.