Effect of Bupleuri Radix extracts on the toxicity of 5-fluorouracil in HepG2 hepatoma cells and normal human lymphocytes.

Abstract

Despite the excellent chemotherapeutic effect of 5-fluorouracil, its cytotoxicity and genotoxicity in normal cells remain a major problem. We sought to assess whether Bupleuri Radix extract enhances 5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cells, while protecting normal blood lymphocytes. Bupleuri Radix, used for treatment of liver disease in oriental medicine, possesses antitumour properties; it induces apoptosis through cell arrest in tumour cells, but does not affect normal lymphocytes. In this study, we evaluated the protective and enhancing effects of Bupleuri Radix on 5-fluorouracil-induced cytotoxicity in HepG2 cells and normal lymphocytes. Treatment with Bupleuri Radix increased the micronuclei frequency and DNA damage, resulting from 5-fluorouracil treatment. However, when human lymphocytes were cotreated with Bupleuri Radix and 5-fluorouracil, the frequency of 5-fluorouracil-induced micronuclei decreased. Although the extent of 5-fluorouracil-induced DNA damage, determined by single-cell gel electrophoresis, increased after treating HepG2 cells with Bupleuri Radix, it decreased in normal lymphocytes. When cells were treated with 20 microM 5-fluorouracil and 200 microg/ml Bupleuri Radix simultaneously, Bax protein increased in HepG2 cells at 24 hr; however, p21 and p53 proteins were up-regulated in normal human lymphocytes. Cotreatment with 200 microg/ml Bupleuri Radix and 20 microM 5-fluorouracil resulted in cell arrest at the late G(1)/early S phase in HepG2 cells (55.80 +/- 0.19%) and normal lymphocytes (97.19 +/- 0.27%). In addition, Bupleuri Radix and 5-fluorouracil treatment increased mitochondria membrane potential collapse only in HepG2 cells (19.02%), while it was not changed in lymphocytes. In conclusion, our findings suggest that Bupleuri Radix may be effective as a therapeutic agent to treat hepatomas.

• Authors: Su Jin Kang, Young Joon Lee, Byeong Mo Kim, Yang Jee Kim, Hae Dong Woo, Hye Kyoung Jeon, Hai Won Chung
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 103 Issue 4 Pg. 305-13 (Oct 2008) ISSN: 1742-7843 [Electronic] England
• PMID: 18834353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Plant Extracts
• Protective Agents
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (pharmacology, toxicity)
• Apoptosis (drug effects, genetics)
• Blotting, Western
• Bupleurum (chemistry)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Comet Assay
• Dose-Response Relationship, Drug
• Drug Synergism
• Fluorouracil (pharmacology, toxicity)
• Gene Expression (drug effects)
• Humans
• Lymphocytes (drug effects, metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Micronuclei, Chromosome-Defective (chemically induced, drug effects)
• Plant Extracts (isolation & purification, pharmacology)
• Protective Agents (isolation & purification, pharmacology)
• Time Factors