Treatment with a New Barbituric Acid Derivative Exerts Antiproliferative and Antimigratory Effects against Sorafenib Resistance in Hepatocellular Carcinoma

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.

LINC00680 enhances hepatocellular carcinoma stemness behavior and chemoresistance by sponging miR-568 to upregulate AKT3

“…6d, Supplementary Figure S5e, f). Mounting data demonstrate that AKT-mTOR and their downstream target molecules such as elF4EBP1 and p70S6K act as positive regulators for HCC progression [18][19][20][21]. In compatible with this, we herein found that LINC00680 knockdown significantly suppressed the phosphorylation of mTOR, elF4EBP1, and p70S6K, whereas overexpression of LINC00680 enhanced their phosphorylation (Fig.…”

Use of a molecular beacon based fluorescent method for assaying uracil DNA glycosylase (Ung) activity and inhibitor screening

“…To show the utility of the method and to investigate their efficiencies towards Mtu Ung, different uracil derivatives were screened to bind to Mtu Ung in terms of thermodynamic parameters [ 33 ] and computational analysis with measure of docking score using Schrödinger Software ( Table 1 ). In addition, barbituric acid was checked owing to its high similarity to the uracil ring and its general applicability in inhibitor design for a variety of targets [ [50] , [51] , [52] , [53] ]. The selected compounds were analysed for dose dependent inhibition.…”

LINC00680 enhances hepatocellular carcinoma stemness behavior and chemoresistance by sponging miR-568 to upregulate AKT3

“…Mounting data demonstrate that AKT-mTOR and their downstream target molecules such as elF4EBP1 and p70S6K act as positive regulators for HCC progression [18][19][20][21]. In compatible with this, we herein found that LINC00680 knockdown signi cantly suppressed the phosphorylation of mTOR, elF4EBP1, and p70S6K, whereas overexpression of LINC00680 enhanced their phosphorylation (Fig.6e).Taken together, these results suggested that miR-568/AKT3/mTOR signaling axis mediated the oncogenic effects of LINC00680 in HCC.…”