Saikosaponin-D enhances radiosensitivity of hepatoma cells under hypoxic conditions by inhibiting hypoxia-inducible factor-1α.

Abstract

BACKGROUND:

Our previous study revealed that the combination of Saikosaponin-d ( SSd) and radiation is more effective in the treatment of liver cancer than the application of either of these monotherapeutic methods. However, the molecular mechanisms of the radiosensitizing effect of SSd on liver cancer remained ill defined.

METHODS:

Cells were treated with different interventions; afterward, cell viability, apoptosis, and cell survival of SMMC-7721 and HepG2 hepatoma cells were examined. Xenograft tumor models were established by subcutaneously injecting SMMC-7721 cells. The molecular mechanism was assessed by western blot.

RESULTS:

SSd dose-dependently increased radiosensitivity of hepatoma cells under hypoxic condition. The growth inhibitory effect of the combined treatment was correlated with cell apoptosis. Further mechanistic analysis indicated that SSd induced the upregulation of p53 and Bax as well as the downregulation of Bcl-2 by attenuating HIF-1α expression under hypoxic condition. These effects were enhanced when the HIF-1α inhibitor PX-478 was introduced. In vivo data also presented a more significant suppression of tumor xenograft growth from the combined therapy than from either of the monotherapeutic methods.

CONCLUSIONS:

Our study provides evidence for a radiosensitizing effect of SSd on hepatoma cells under hypoxic conditions by inhibiting HIF-1α expression. Thus, SSd can be used as a potential sensitizer in hepatoma radiotherapy. © 2014 S. Karger AG, Basel.

• Authors: Bao-Feng Wang, Xi-Jing Wang, Hua-Feng Kang, Ming-Hua Bai, Hai-Tao Guan, Zhong-Wei Wang, Ying Zan, Ling-Qin Song, Wei-Li Min, Shuai Lin, Yan-An Cheng
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 33 Issue 1 Pg. 37-51 ( 2014) ISSN: 1421-9778 [Electronic] Germany
• PMID: 24401554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Saponins
• Tumor Suppressor Protein p53
• Vascular Endothelial Growth Factor A
• bcl-2-Associated X Protein
• Oleanolic Acid
• saikosaponin D

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (metabolism, pathology)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Liver Neoplasms (metabolism, pathology)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Oleanolic Acid (analogs & derivatives, chemistry, pharmacology)
• Radiation Tolerance (drug effects)
• Saponins (chemistry, pharmacology)
• Tumor Stem Cell Assay
• Tumor Suppressor Protein p53 (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (metabolism)