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

PLoS One. 2014 Dec 8;9(12):e113479. doi: 10.1371/journal.pone.0113479. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / metabolism
  • Disease Models, Animal
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Protein Binding
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Burden / drug effects
  • Ursodeoxycholic Acid / analogs & derivatives
  • Ursodeoxycholic Acid / chemistry
  • Ursodeoxycholic Acid / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cyclins
  • Ursodeoxycholic Acid
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Cyclin-Dependent Kinases

Grants and funding

Funding was provided by Fundamental Research Funds for the Central Universities (No. 2010121100, 2011121055), the Grants from the National Natural Science Foundation of China (No. 81202419, 81202956), Xiamen Science and Technology Key program grant (No. 3502Z20100006) and the Natural Science Foundation of Fujian Province of China (No. 2011 J05098). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.