State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Toxicol Lett. 2012 Jul 20;212(2):113-25. doi: 10.1016/j.toxlet.2012.05.008. Epub 2012 May 17.
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.
肝细胞癌 (HCC) 是一种难治性恶性肿瘤，发病率高，死亡率高。目前 HCC 的化疗策略侧重于开发疗效更好、毒性更低的药物。在本研究中，我们证明天然黄酮类化合物白杨素 A 优先抑制 HCC 细胞系 HepG2 的活力，而对正常肝细胞系 L02 没有影响。在 HepG2 细胞中，但不是在 L02 细胞中，白杨素 A 诱导大量的细胞内 H₂O₂产生和未折叠蛋白反应 (UPR) 途径 PERK-eIF2α-ATF4-CHOP 分支的过度激活，导致 TRB3 的诱导和 p-AKT1/2/3（Ser473）的因果减少。此外，这些作用可以通过 CHOP 的稳定敲低或预处理然后与特定的 H₂O₂清除剂过氧化氢酶共同孵育来消除。这些结果表明，UPR 途径的 H₂O₂触发过度激活和 AKT 信号的因果失活导致白杨素 A 在恶性 HepG2 细胞中的优先细胞毒性。因此，本研究提出了一个潜在的分子机制，暗示了白杨素 A 的选择性抗肿瘤作用，并推荐白杨素 A 作为改善目前治疗 HCC 的化疗策略的前景。
