6H2L, a novel synthetic derivative of bifendate, induces apoptosis in hepatoma cells via mitochondrial and MAPK pathway

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Our previous study indicated that 6H2L, a novel synthetic bifendate derivative, shows multidrug resistance reversal activity, while its antitumor effect has not been revealed. Here, the potent antitumor effects of 6H2L on hepatoma cells both in vitro and in vivo were investigated. 6H2L inhibited cell viability of HepG2 and SMMC-7721 cells with less sensitivity to normal human liver L-02 cells. 6H2L induced apoptosis in hepatoma cells. It upregulated Bax expression, while simultaneously decreasing Bcl-2 expression. Further elucidation of the mechanism revealed that 6H2L induced mitochondrial dysfunction, with transmitochondrial membrane potential collapse and cytochrome c release, which activated caspase-9 and caspase-3 and subsequently cleaved PARP, suggesting that 6H2L induced apoptosis via triggering mitochondrial pathway. Moreover, 6H2L decreased the phosphorylation of ERK1/2, whereas it increased the expression of p-JNK and p-p38. Then, specific inhibitors of the mitogen-activated protein kinase (MAPK) pathway were employed to confirm the roles of the MAPK pathway in the apoptosis-inducing effects of 6H2L. Additionally, 6H2L obviously inhibited the tumor growth in H22-bearing ICR mice. Meanwhile, 6H2L remarkably up-regulated Bax while suppressing Bcl-2 in tumors. Importantly, neither significant weight loss, white blood cell (WBC) count, nor histopathological abnormalities of major organs were observed in the mice receiving 6H2L treatment, indicating that 6H2L exerted strong anticancer activities with low toxicity in vivo. In contrast, fluorouracil inhibited tumor growth with significant decreased body weight and WBC count. Taken together, these results suggested 6H2L is a potential therapeutic candidate for HCC.

Keywords: 6H2L; Apoptosis; Hepatocellular carcinoma; MAPK pathway; Mitochondria.