Disruption of the PI3K/AKT/mTOR signaling cascade and induction of apoptosis in HL-60 cells by an essential oil from Monarda citriodora

- We have isolated an essential oil (MC) from Monarda citriodora.
- MC is a rich source of thymol.
- Both MC and thymol inhibit PI3K/Akt/mTOR pathway.
- MC and thymol induce extrinsic and intrinsic apoptosis.
- The present study highlight the importance of essential oil as anticancer agent.

We have isolated an essential oil from Monarda citriodora (MC) and characterized its 22 chemical constituents with thymol (82%), carvacrol (4.82%), β-myrcene (3.45%), terpinen-4-ol (2.78%) and p-cymene (1.53%) representing the major constituents. We have reported for the first time the chemotherapeutic potential of MC in human promyelocytic leukemia HL-60 cells by means of apoptosis and disruption of the PI3K/AKT/mTOR signaling cascade. MC and its major constituent, thymol, inhibit the cell proliferation in different types of cancer cell lines like HL-60, MCF-7, PC-3, A-549 and MDAMB-231. MC was found to be more cytotoxic than thymol in HL-60 cells with an IC50 value of 22 μg/ml versus 45 μg/ml for thymol. Both MC and thymol induce apoptosis in HL-60 cells, which is evident by Hoechst staining, cell cycle analysis and immuno-expression of Bcl-xL, caspase-3,-8,-9 and PARP-1 cleavage. Both induce apoptosis by extrinsic and intrinsic apoptotic pathways that were confirmed by enhanced expression of death receptors (TNF-R1, Fas), caspase-9, loss of mitochondrial membrane potential and regression of Bcl-2/Bax ratio. Interestingly, both MC and thymol inhibit the downstream and upstream signaling of PI3K/AKT/mTOR pathway. The degree of apoptosis induction and disruption of the PI3K signaling cascade by MC was significantly higher when compared to thymol.