Liver Cancer
Copyright ©The Author(s) 2005. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 28, 2005; 11(36): 5633-5637
Published online Sep 28, 2005. doi: 10.3748/wjg.v11.i36.5633
Synergistic effect of all-trans-retinoic acid and arsenic trioxide on growth inhibition and apoptosis in human hepatoma, breast cancer, and lung cancer cells in vitro
Le-Min Lin, Bao-Xin Li, Jian-Bing Xiao, Dan-Hua Lin, Bao-Feng Yang
Le-Min Lin, Department of General Surgery, The First Clinical College, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Bao-Xin Li, Jian-Bing Xiao, Dan-Hua Lin, Bao-Feng Yang, Department of Pharmacology, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Author contributions: All authors contributed equally to the work.
Supported by the Key Scientific and Technological Projects of Heilongjiang Province during the 10th Five-Year Plan Period, No. GB05C401-10
Correspondence to: Dr. Bao-Feng Yang, Department of Pharmacology, Harbin Medical University, Harbin 150086, Heilongjiang Province, China. yangbf@cms.hrbmu.edu.cn
Telephone: +86-451-86671354 Fax: +86-451-86699644
Received: January 14, 2005
Revised: April 1, 2005
Accepted: April 2, 2005
Published online: September 28, 2005
Abstract

AIM: To investigate the effect of all-trans-retinoic acid (ATRA) on arsenic trioxide (As2O3)-induced apoptosis of human hepatoma, breast cancer, and lung cancer cells in an attempt to find a better combination therapy for solid tumors.

METHODS: Human hepatoma cell lines HepG2, Hep3B, human breast cancer cell line MCF-7, and human lung adenocarcinoma cell line AGZY-83-a were treated with As2O3 together with ATRA. Cell survival fraction was determined by MTT assay, cell viability and apoptosis were measured by annexin V-fluorescein isothiocyanate (FITC) and PI staining, and intracellular glutathione (GSH) and glutathione-S-transferase (GST) activities were determined using commercial kits.

RESULTS: Cytotoxicity of ATRA was low. ATRA (0.1, 1, and 10 μmol/L) could synergistically potentiate As2O3 to exert a dose-dependent inhibition of growth and to induce apoptosis in each of the cell lines. HepG2 and Hep3B with low intracellular GSH or GST activities were remarkably sensitive to As2O3 or As2O3+ATRA, while AGZY-83-a with higher GSH or GST activities was less sensitive to As2O3 or As2O3+ATRA. Treatment with 2 μmol/L As2O3 for 72 h significantly decreased intracellular GSH and GST levels in each of the cell lines, and 1 μmol/L ATRA alone reduced minimal intracellular GSH and GST levels. ATRA potentiated the effect of As2O3 on intracellular GSH levels, but intracellular GST levels were not significantly affected by the combination of As2O3 and ATRA for 72 h as compared to As2O3 alone.

CONCLUSION: ATRA can strongly potentiate As 2O3-induced growth-inhibition and apoptosis in each of the cell lines, and two drugs can produce a significant synergic effect. The sensitivity to As2O3 or As2O3+ATRA is inversely proportional to intracellular GSH or GST levels in each of the cell lines. The GSH redox system may be the possible mechanism by which ATRA synergistically potentiates As2O3 to exert a dose-dependent inhibition of growth and to induce apoptosis.

Keywords: Arsenic trioxide; All-trans-retinoic acid; Hepatocellular carcinoma; Cancer of breast and lung; Glutathione; Glutathione-S-transferase