Impact of Alpha-mangostin on human esophageal adenocarcinoma cells reveals activation of key apoptotic signaling pathways.

Current chemotherapeutic modalities for the clinical management of esophageal adenocarcinoma, do not, in most cases, result in complete remission and also elicit adverse side effects. In this context, active entities from natural products that have anticancer activity need to be developed. These drugs could also have the benefit of fewer side effects. We opted to study the effects of alpha-Mangostin (α-Mangostin), a highly purified single entity belonging to the xanthone family of compounds on human esophageal adenocarcinoma cells. To this end, we investigated its effect on OE33 and FLO-1 human esophageal adenocarcinoma cells. α-Mangostin exhibited inhibition of cell viability in a dose dependent manner in both the cell lines. We also assessed the inhibitory activity of isoforms of α-Mangostin namely, β-Mangostin and γ-Mangostin on OE33 cells. γ-Mangostin had inhibitory potential similar to α-Mangostin, whereas β-Mangostin was comparatively less inhibitory. Therefore, detailed studies were carried out with α-Mangostin. Clonogenic assay revealed its impact on the proliferation potential of OE33 cells as evidenced by reduction in the number of colonies, suggesting a sustained response even after withdrawal of the treatment. Notably, analysis of the signaling pathways revealed apoptosis induction mediated by multicaspase and executioner caspases 3/7 as the major contributors for the inhibitory activity. Results from the combinatorial studies of α-Mangostin with currently used chemotherapeutics, Cisplatin and 5-Fluorouracil (5-FU) suggested that the anticancer activity was maintained in combined treatments. As α-Mangostin has a different mode of action to that of Cisplatin and 5-FU, therapeutic approaches combining these modalities may have beneficial outcomes as well as potentially impede the development of chemoresistance.