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Synergistic effect of all-trans-ret inoic acid and arsenic trioxide on growth inhibition and apoptosis in human hepatoma, breast cancer, and lung cancer cells in vitro

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World Journal of Gastroenterology 2005年第36期11卷 5633-5637页

作者： Le-Min Lin Bao-Xin Li Jian-Bing Xiao Dan-Hua Lin Bao-Feng Yang Department of General Surgery The First ClinicalCollege Harbin Medical University Harbin 150001 Heilongjiang Province China Department of Pharmacology Harbin Medical University Harbin150086 Heilongjiang Province China

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 As203 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 ***： ATRA can strongly potentiate As2O3- 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 As203 to exert a dose-dependent inhibition of growth and to induce apoptosis. 2005 The WJG Press and Els

关键词： Arsenic trioxide aii-trans-retinoic acid Hepatocellular carcinoma Cancer of breast and lung Glutathione Glutathione-S-tra nsferase

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