Potentiation of the antitumor effects of both selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors in human hepatic cancer cells by inhibition of the MEK/ERK pathway
| Autor: | Giuseppe Montalto, Natale D'Alessandro, Antonina Azzolina, Nadia Lampiasi, Daniela Foderà, Melchiorre Cervello, Antonella Cusimano |
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| Přispěvatelé: | CUSIMANO, A, FODERA' D, D'ALESSANDRO, N, LAMPIASI, N, AZZOLINA, A, MONTALTO, G, CERVELLO, M |
| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Carcinoma Hepatocellular Time Factors Blotting Western Apoptosis Pharmacology COX-1 COX-2 NSAIDs MEK1/2 ERK1/2 Nitriles Butadienes Tumor Cells Cultured Humans Cyclooxygenase Inhibitors Sulfones Enzyme Inhibitors Phosphorylation Protein kinase A Cell Proliferation chemistry.chemical_classification Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinase 3 biology Dose-Response Relationship Drug Liver Neoplasms Cytochromes c Long-term potentiation Drug Synergism Isoxazoles Flow Cytometry Enzyme Oncology chemistry Cyclooxygenase 2 Caspases Cancer cell biology.protein Cyclooxygenase 1 Molecular Medicine MEK-ERK Pathway Pyrazoles Drug Therapy Combination Cyclooxygenase Hepatoma cell |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 1555-8576 |
| Popis: | The molecular mechanisms behind the anti-neoplastic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are not completely understood and cannot be explained by the inhibition of the cyclooxygenase (COX) enzymes COX-1 and COX-2 alone. We previously reported that both the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor CAY10404 exhibit anti-tumor effects in human hepatoma cells. NSAID inhibitors have many COX-independent actions and, among others, the mitogen-activated protein kinase (MAPK) pathways are targets for NSAIDs. Here, we examined the role of MEK/ERK1/2 signaling in the anti-neoplastic effects of both selective COX-1 and COX-2 inhibitors in two human hepatoma cell lines. Treatment of hepatoma cells with the selective COX-1 inhibitor SC-560, as well as with the selective COX-2 inhibitor CAY10404, was associated with activation of ERK1/2 in a time- and dose-dependent manner. Treatment with COX-1 and COX-2 inhibitors in the presence of the selective MEK1/2 inhibitor U0126 effectively suppressed ERK1/2 activation and combinations of either SC-560 or CAY10404 with U0126 resulted in synergistic effects on cell growth inhibition and induction of apoptosis. In HuH-6 hepatoma cells the combination-induced apoptosis was associated with caspase-9 and -3 activation, PARP cleavage, release of cytochrome c from the mitochondria into the cytosol and down-regulation of survivin and beta-catenin levels. In conclusion, our study showed that growth inhibitory concentrations of selective COX-1 and COX-2 inhibitors increased ERK1/2 phosphorylation in hepatoma cells, and that inhibition of the MEK/ERK signaling pathway potentiates the antitumor activity of both types of inhibitors. Therefore, our results provide preclinical support for a combined chemotherapeutic approach with selective NSAIDs and MEK inhibitors for the treatment of hepatocellular carcinoma. |
| Databáze: | OpenAIRE |
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