Natural borneol, a monoterpenoid compound, potentiates selenocystine-induced apoptosis in human hepatocellular carcinoma cells by enhancement of cellular uptake and activation of ROS-mediated DNA damage

PLoS One. 2013 May 20;8(5):e63502. doi: 10.1371/journal.pone.0063502. Print 2013.

Abstract

Selenocystine (SeC) has been identified as a novel compound with broad-spectrum anticancer activities. Natural borneol (NB) is a monoterpenoid compound that has been used as a promoter of drug absorption. In the present study, we demonstrated that NB significantly enhanced the cellular uptake of SeC and potentiated its antiproliferative activity on HepG2 cells by induction of apoptosis. NB effectively synergized with SeC to reduce cancer cell growth through the triggering apoptotic cell death. Further mechanistic studies by Western blotting showed that treatment of the cells with NB and SeC activated the intrinsic apoptotic pathway by regulation of pro-survival and pro-apoptotic Bcl-2 family proteins. Treatment of the cells with NB and SeC induced the activation of p38MAPK and inactivation of Akt and ERK. NB also potentiated SeC to trigger intracellular ROS generation and DNA strand breaks as examined by Comet assay. Moreover, the thiol-reducing antioxidants effectively blocked the occurrence of cell apoptosis, which confirmed the important role of ROS in cell apoptosis. Taken together, these results reveal that NB strongly potentiates SeC-induced apoptosis in cancer cells by enhancement of cellular uptake and activation of ROS-mediated DNA damage. NB could be further developed as a chemosensitizer of SeC in treatment of human cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Camphanes / pharmacology*
  • Carcinoma, Hepatocellular
  • Caspases / metabolism
  • Cell Proliferation / drug effects
  • DNA Damage
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Enzyme Activation
  • Hep G2 Cells
  • Humans
  • MAP Kinase Signaling System
  • Mitochondria / drug effects
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reactive Oxygen Species / metabolism*
  • Selenocysteine / metabolism
  • Selenocysteine / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Camphanes
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Selenocysteine
  • Caspases
  • isoborneol

Grant support

This work was supported by the National Natural Science Foundation of China (31101278, 31130042, 21271002 and 21201082) and Guangdong Province, 973-plan (2012CB720800), the national science and technology support program (2012BAD37B01), the Doctoral Foundation of Ministry of Education of China, and the Research Fund for the Doctoral Program of Higher Education of China (20110172120033). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.