Alphitolic acid, an anti-inflammatory triterpene, induces apoptosis and autophagy in oral squamous cell carcinoma cells, in part, through a p53-dependent pathway

The antitumour mechanism of alphitolic acid (ALA), an anti-inflammatory triterpene, in oral squamous cell carcinoma (OSCC) cells was investigated. ALA suppressed the proliferation of SCC4 and SCC2095 OSCC cells with IC₅₀ values of 12 and 15 μM, respectively, via apoptotic induction. Mechanistically, this drug effect on apoptosis was, in part, associated with its ability to block Akt-NF-κB signalling. Moreover, ALA induced autophagy, as evidenced by increased expression of the autophagy biomarkers Beclin 1, Atg7, and LC3B-II, and autophagosome formation. This autophagy induction played a protective role as autophagy inhibitors enhanced cellular susceptibility to ALA-induced apoptosis. Also noteworthy is the involvement of p53 in ALA-mediated cytotoxicity. ALA increased p53 phosphorylation/expression, accompanied by parallel decreases in the expression of the oncogenic E3 ligase MDM2, and shRNA-mediated knockdown of p53 partially rescued ALA-mediated cytotoxicity. Together, these findings suggest the translational value of ALA as an ingredient in functional food/dietary supplement for OSCC prevention.