Strategy to enhance the therapeutic effect of doxorubicin in human hepatocellular carcinoma by selenocystine, a synergistic agent that regulates the ROS-mediated signaling.

Abstract

Doxorubicin-based chemotherapy represents one of the most effective ways in combating human cancers. However, its clinical use is limited by severe side effects. Selenocystine (SeC) is a natural available selenoamino acid with novel anticancer efficacy. In this study, we used SeC to sensitize HepG2 human hepatocellular carcinoma (HCC) cells to DOX, and to achieve anticancer synergism in vitro and in vivo. Treatment with DOX dose-dependently reduced HepG2 cell viability through initiating cell apoptosis and strong G2/M phase cell cycle arrest. Mechanistic studies indicated that this sensitization of SeC to DOX was achieved by triggering inactivation of ERK and AKT and DNA damage through reactive oxygen species (ROS) overproduction. Pretreatment with inhibitors of ERK and AKT markedly enhanced combined treatment-induced cell killing, indicating that combined treatment-induced HCC cell killing with ERK- and AKT-dependent manner. Furthermore, inhibition of ROS effectively attenuated combined treatment-induced DNA damage and inactivation of ERK and AKT. Additionally, xenograft hepatocellular carcinoma growth was also effectively inhibited by combined treatment through induction of cell apoptosis in vivo. Taken together, our results suggest that the strategy to use SeC and DOX in combination could be a highly efficient way to achieve anticancer synergism against HCC.

• Authors: Cundong Fan, Wenjie Zheng, Xiaoyan Fu, Xiaoling Li, Yum-Shing Wong, Tianfeng Chen
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 9 Pg. 2853-63 (May 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24797310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Antiviral Agents
• Organoselenium Compounds
• Reactive Oxygen Species
• selenocystine
• Cystine
• Doxorubicin
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Antiviral Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cystine (analogs & derivatives, pharmacology)
• DNA Damage (drug effects)
• Doxorubicin (pharmacology)
• Drug Therapy, Combination
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Nude
• Organoselenium Compounds (pharmacology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays