Hepatocellular carcinoma is the fifth most common and the third most lethal cancer worldwide. In recent years, natural flavonoids have drawn great attention as repository for the exploitation of novel antineoplastic agents. 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC), a functional chalcone isolated from the buds of Cleistocalyx operculatus, has been reported to exert potent cytotoxicity against multi-drug resistant BEL-7402/5-FU cells. In this study, the precise mechanisms of DMC-mediated growth inhibition in BEL-7402/5-FU cells were further investigated. DMC was found to trigger apoptosis predominantly via the mitochondria-dependent pathway and the enhancement of reactive oxygen species (ROS) generation. Meanwhile, DMC induced G1 cell cycle arrest through downregulation of cyclin D1 and CDK4. Furthermore, DMC increased p53 level and inhibited NF-κB nuclear-localization via suppression of PI3K/AKT signaling axis, which might be the underlying mechanism of DMC-induced apoptosis and cell cycle arrest in BEL-7402/5-FU cells. Collectively, the study elucidated the mechanisms by which DMC may inhibit the growth of BEL-7402/5-FU cells and suggested the possibility that DMC might be a promising candidate therapeutic agent for hepatoma treatment in the future.

肝细胞癌是全球第五大最常见和致命性第三大癌症。近年来，天然类黄酮作为用于开发新型抗肿瘤药的储存库引起了极大的关注。2'，4'-二羟基-6'-甲氧基-3'，5'-二甲基查尔酮（DMC），一种分离自沙枣（Cleistocalyx operculatus）芽中的功能查尔酮据报道，其对多药耐药的BEL-7402 / 5-FU细胞发挥有效的细胞毒性作用。在这项研究中，进一步研究了DMC介导的BEL-7402 / 5-FU细胞生长抑制的确切机制。发现DMC主要通过线粒体依赖性途径和增强活性氧（ROS）生成来触发凋亡。同时，DMC通过下调细胞周期蛋白D1和CDK4诱导G1细胞周期停滞。此外，DMC通过抑制PI3K / AKT信号轴而增加p53水平并抑制NF-κB核定位，这可能是DMC诱导BEL-7402 / 5-FU细胞凋亡和细胞周期停滞的潜在机制。总的来说，