Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer death worldwide. Sorafenib, a multikinase inhibitor, is the first-line drug approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced HCC. However, most patients who continuously receive sorafenib may acquire resistance to this drug. Therefore, it is important to develop a new compound to treat liver cancer and sorafenib-resistant liver cancer. Barbituric acid derivatives have been used as antiasthmatic drugs in the clinic. We previously reported that a novel barbituric acid derivative inhibited carbon tetrachloride-induced liver fibrosis in mice, but its effects on liver cancer remain unknown. Thus, the purpose of this study was to investigate the antitumor effect of barbituric acid derivatives on HCC cells and sorafenib-resistant HCC cells (HCC-SRs). Our findings reveal that one of the barbituric acid derivatives, BA-5, significantly inhibited HCC and HCC-SR cell viability in a dose- and time-dependent manner. Therefore, compound BA-5 was selected for further experiments. Western blot data revealed that BA-5 treatment decreased the phosphorylation of AKT/p70s6k without affecting the MAPK pathway and increased cleaved PARP and cleaved caspase-7 in both HCC and HCC-SR cells. Since epithelial-mesenchymal transition plays a significant role in regulating cancer invasion and migration, we used the wound healing assay to evaluate the antimigratory effect of compound BA-5. The results showed that BA-5 treatment inhibited HCC and HCC-SR cell migration and reduced Vimentin protein expression. These results were confirmed by microarray analysis showing that BA-5 treatment influenced cancer cell motility and growth-related pathways. In the xenograft mouse model experiment, BA-5 administration significantly inhibited HCC cancer cell growth in mice. Furthermore, the combination of BA-5 with a low dose of regorafenib synergistically inhibited HCC-SR cell proliferation. In conclusion, our study showed that the barbituric acid derivative BA-5 is a new candidate for HCC and sorafenib-resistant HCC therapy.
Highlights
Liver cancer is the leading cause of cancer-associated death [1]
The results showed we used four different hepatocellular carcinoma (HCC) cell lines, SK-Hep 1, HepG2, Huh7, and Hep3B and two sorafenib-resistant that cells with for 72inhthe had the mostThe significantly inhibited cell treated viability in BA-5 all four results showed that cells with for cell lines and two sorafenib-resistant cells compared with that of the other candidates
To study the mechanisms underlying the antiproliferative effect of compound BA-5 in HCC and HCC-SR cells, we examined protein phosphorylation in both the AKT and mitogen-activated protein kinase (MAPK) signaling pathways
Summary
Liver cancer consists of a diverse group of malignant tumors, which include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and other tumors. HCC comprises 70–80% of cases [2]. The risk factors of cirrhosis, which include viral hepatitis, such as Hepatitis B virus infection, and HCV infection, and alcohol consumption [3], can be the most common cause for developing HCC because a great number of HCCs evolve from hepatic cirrhosis [4]. Other main risk factors associated with HCC patients include non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis [5]. The development of HCC is complex and includes cancer cell proliferation and metastasis [6]. Most HCC patients are diagnosed with advanced stage disease and are not eligible for surgery. Sorafenib is a first-line systemic therapy approved for the treatment of advanced HCC by the U.S Food and Drug Administration (FDA). Sorafenib is an orally administered multikinase inhibitor that decreases tumor cell proliferation by blocking Raf-1, wild-type
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