Toxicology letters

Activation of the unfolded protein response contributed to the selective cytotoxicity of oroxylin A in human hepatocellular carcinoma HepG2 cells.

PMID 22609744


Hepatocellular carcinoma (HCC) is a refractory malignancy with a high incidence and large mortality. Current strategy for the chemotherapy of HCC focuses on developing agents with better efficacy and lower toxicity. In this study, we demonstrated that the natural flavonoid oroxylin A preferentially inhibited the viability of HCC cell line HepG2 but not the normal hepatic cell line L02. In HepG2 but not L02 cells, oroxylin A induced substantial production of intracellular H₂O₂ and inordinate activation of the PERK-eIF2α-ATF4-CHOP branch of the unfolded protein response (UPR) pathway, which resulted in the induction of TRB3 and causal reduction of p-AKT1/2/3 (Ser473). Moreover, these effects were eliminated by either the stable knockdown of CHOP or the pretreatment and then co-incubation with the specific H₂O₂ scavenger catalase. These results indicated that the H₂O₂-triggered overactivation of the UPR pathway and causal inactivation of AKT signaling contributed to the preferential cytotoxicity of oroxylin A in malignant HepG2 cells. Therefore, present study proposed an underlying molecular mechanism that implicated the selective antitumor effect of oroxylin A and recommended oroxylin A as a prospect for improving the current chemotherapeutic strategy for the treatment of HCC.