Inhibitory effects of patchouli alcohol on hepatocellular carcinoma growth through accumulation of oxidative stress and inactivation of androgen receptor signaling.

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed malignancies and exhibits a high mortality rate. Patchouli alcohol (PA) is a tricyclic sesquiterpene derived from Pogostemon cablin, and the present study evaluated the antihepatoma capacity of PA and described a potential strategy for its combination with sorafenib (SOR) in vitro and in vivo. The anticancer potential of PA against HCC was evaluated using the MTT assay, flow cytometry, western blotting, DCF-DA and JC-1 staining, TUNEL assay, immunofluorescence and immunohistochemistry staining, and migration and invasion assays. The results indicated that PA suppressed HCC growth by inducing reactive oxygen species (ROS) generation, mitochondrial membrane potential imbalance, and DNA damage, ultimately resulting in cell cycle arrest and apoptosis via the activation of p53/p21 and also extrinsic (Fas/FasL/caspase-8), intrinsic (Bax/Bcl2/caspase-9), and caspase-independent pathways. The combination of PA with SOR exhibited synergistic effects, exerted survival benefits, and improved the lifespan of mice at well-tolerated doses. Furthermore, PA targets the androgen receptor (AR) to inhibit dihydrotestosterone-induced (DHT)-induced cell proliferation, AR translocation to the nucleus, and downstream gene expression during HCC growth. On the whole, PA alone or in combination with SOR exhibited markedly improved therapeutic efficacy in HCC by blocking AR-mediated and multiple other signaling pathways. Therefore, this study provides an experimental basis for the evaluation of PA as an alternative drug (alone or in combination) for the treatment of HCC.