Mecambridine induces potent cytotoxic effects, autophagic cell death and modulation of the mTOR/PI3K/Akt signaling pathway in HSC-3 oral squamous cell carcinoma cells.

Plant secondary metabolites including alkaloids, demonstrate a complex diversity in their molecular scaffolds and exhibit tremendous pharmacological potential as anti-cancerous therapeutics. The present study aimed to evaluate the anticancer activity of a natural alkaloid, mecambridine, against human oral squamous cell carcinoma (OSCC). An MTT assay was used to evaluate cytotoxic effects of mecambridine on HSC-3 oral squamous cell carcinoma cells. Effects of mecambridine on autophagy-associated proteins were analyzed by western blotting. Effects on reactive oxygen species (ROS) and mitochondrial membrane potential were assessed by flow cytometry. Results indicated that mecambridine exhibited an IC50 value of 50 µM and exerted its cytotoxic effects in a dose dependent manner on OSCC HSC-3 cells. Furthermore, it was observed that mecambridine decreases cell viability and induces autophagy in a dose-dependent manner. The underlying mechanism for the induction of autophagy was demonstrated to be associated with ROS-mediated alterations in mitochondrial membrane potential and modulation of the mechanistic target of rapamycin/phosphoinositide 3-kinase/protein kinase B (m-TOR/PI3K/Akt) signaling pathway in HSC-3 at the IC50. In conclusion, the present study suggests that mecambridine exhibits substantial anticancer activity against OSCC HSC-3 cells by induction of autophagy and modulates the expression of the mTOR/PI3K/Akt signaling cascade which is considered a potential target pathway for anti-cancer agents.