Eucalyptol targets PI3K/Akt/mTOR pathway to inhibit skin cancer metastasis.

Eucalyptol (EU) is a monoterpenoid found as an active compound of many plants such as bay leaves, cardamom and is also found as a major constituent in eucalyptus oil. Although the anticancer activity of eucalyptol (EU) has been reported in a few cancer cell lines, its effect on tumor metastasis has not been studied so far. Here, we have shown that the EU has anti-metastatic activity against skin cancer cells in vitro and in vivo. EU decreases migration and invasion of skin cancer cells. Further, it reduces the expression of mesenchymal markers vimentin, snail, slug, twist, and induces the expression of epithelial marker, E-cadherin which indicates that it reverses the epithelial to mesenchymal transition. Gelatin zymography shows that the EU reduces the activity of MMP2 and MMP9. Furthermore signaling study by molecular docking and western blotting shows that EU modulates PI3K/Akt/mTOR signaling pathway. The reduction in the expression of PI3K/Akt/mTOR was enhanced by the use of the PI3K inhibitor, LY294002. In vivo, the anti-metastatic potential of EU was confirmed in C57BL/6 mouse. In conclusion, the EU inhibits migration and invasion of skin cancer by modulating PI3K/Akt/mTOR pathway both in in vitro and in vivo and might provide a new therapeutic approach in skin cancer.