U12, a UDCA derivative, acts as an anti-hepatoma drug lead and inhibits the mTOR/S6K1 and cyclin/CDK complex pathways.

Yang Xu,Cuiling Sun,Dequan Zeng,Xiao-Kun Zhang,Zhiping Zeng,Haifeng Chen,Guanghui Wang,Rong Ding,Ting Lin,Qiang Luo

doi:10.1371/journal.pone.0113479

Yang Xu, Cuiling Sun + Show 8 more

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https://doi.org/10.1371/journal.pone.0113479

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Abstract

U12, one of 20 derivatives synthesized from ursodeoxycholic acid (UDCA), has been found to have anticancer effects in liver cancer cell lines (SMMC-7721 and HepG2) and to protect normal liver cells from deoxycholic acid (DCA) damage (QSG-7701). Its anticancer mechanism was investigated using computer-aided network pharmacology and comparative proteomics. Results showed that its anti-malignancy activities were activated by mTOR/S6K1, cyclinD1/CDK2/4 and caspase-dependent apoptotic signaling pathways in hepatocellular carcinoma cells (HCC). The action of U12 may be similar to that of rapamycin. Animal testing confirmed that U12 exerted better anti-tumor activity than UDCA and had less severe side effects than fluorouracil (5-Fu). These observations indicate that U12 differs from UDCA and other derivatives and may be a suitable lead for the development of compounds useful in the treatment of HCC.

Highlights

Hepatocellular carcinoma (HCC) accounts for 75–90% of all cases of liver cancer in most countries
Cytotoxicity of ursodeoxycholic acid (UDCA) derivatives to normal and liver cancer cell lines An MTT assay was used to investigate the effects of UDCA and its derivatives on the viability of SMMC-7721, HepG2, and QSG-7701 (Fig. 2A–C)
Considering UDCA can antagonize deoxycholic acid (DCA)-induced impairment to different extents depending on the conditions, whether U12 may prevent the action of DCA was here evaluated [21, 22]

Summary

Introduction

Hepatocellular carcinoma (HCC) accounts for 75–90% of all cases of liver cancer in most countries. HCC is the sixth most common cancer in the world and it is especially common in Africa, southeast Asia, and China [1]. The majority of cases of HCC arise against a background of chronic liver disease, including hepatitis B virus (HBV) and hepatitis C virus (HCV), or ethanol abuse. U12 and Anti-Hepatoma Drug Lead of HCC is growing in the U.S and some European countries [1, 2]. These factors have intensified research efforts into new treatment strategies, there still are few effective drugs without drug resistance. Sorafenib (previously known as BAY 43-9006) is the only drug approved for the treatment for HCC by the Food and Drug Administration of the United States

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