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.
|Data di pubblicazione:||2007|
|Titolo:||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|
|Autori:||CUSIMANO, A; FODERA' D; D'ALESSANDRO, N; LAMPIASI, N; AZZOLINA, A; MONTALTO, G; CERVELLO, M|
|Tipologia:||Articolo su rivista|
|Citazione:||CUSIMANO, A., FODERA' D, D'ALESSANDRO, N., LAMPIASI, N., AZZOLINA, A., MONTALTO, G., et al. (2007). 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. CANCER BIOLOGY & THERAPY, 6, 1461-1468.|
|Tipo:||Articolo in rivista|
|Appare nelle tipologie:||01 - Articolo su rivista|