Synergistic Effects of Acyclic Retinoid and OSI-461 on Growth Inhibition and Gene Expression in Human Hepatoma Cells
| Autor: | Julia H. Hayes, Kyriakos P. Papadopoulos, Masumi Suzui, Atsuko Deguchi, I. Bernard Weinstein, Jin T. E. Lim, Masahito Shimizu, Danhua Xiao |
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| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
Receptors Retinoic Acid Intracellular Space Retinoic acid Apoptosis Cell Cycle Proteins Retinoic acid receptor beta Retinoblastoma Protein chemistry.chemical_compound Sulindac Cyclin D1 Retinoid Phosphorylation Promoter Regions Genetic Cyclic GMP beta Catenin Reverse Transcriptase Polymerase Chain Reaction Liver Neoplasms Microfilament Proteins Drug Synergism Gene Expression Regulation Neoplastic Oncology Growth inhibition Chloramphenicol O-Acetyltransferase Cyclin-Dependent Kinase Inhibitor p21 Carcinoma Hepatocellular medicine.drug_class Recombinant Fusion Proteins Blotting Western Antineoplastic Agents Tretinoin Biology Response Elements Transfection Models Biological Resting Phase Cell Cycle Exisulind Cell Line Tumor medicine Humans RNA Messenger Cell Proliferation Dose-Response Relationship Drug G1 Phase Phosphoproteins Cytoskeletal Proteins chemistry Cancer cell Trans-Activators Cancer research Tumor Suppressor Protein p53 Cell Adhesion Molecules |
| Zdroj: | Clinical Cancer Research. 10:6710-6721 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-04-0659 |
| Popis: | Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 μmol/L acyclic retinoid and 0.01 μmol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21CIP1 protein and mRNA, and stimulated p21CIP1 promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor β and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21CIP1 and retinoic acid receptor β expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies. |
| Databáze: | OpenAIRE |
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