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Research Paper
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
Antonella Cusimano, Daniela Foderà, Natale D'Alessandro, Nadia Lampiasi, Antonina Azzolina, Giuseppe Montalto and Melchiorre Cervello
volume 6 | issue 9
September 2007Pages: 1461 - 1468
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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 β-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.
Authors
Antonella Cusimano
Istituto di Biomedicina e Immunologia Molecolare Alberto Monroy, Consiglio Nazionale delle Ricerche, Palermo, Italy
Daniela Foderà
Istituto di Biomedicina e Immunologia Molecolare Alberto Monroy, Consiglio Nazionale delle Ricerche, Palermo, Italy
Natale D'Alessandro
Dipartimento di Scienze Farmacologiche, Università Palermo, Palermo, Italy
Nadia Lampiasi
aIstituto di Biomedicina e Immunologia Molecolare Alberto Monroy, Consiglio Nazionale delle Ricerche, Palermo, Italy
Antonina Azzolina
Istituto di Biomedicina e Immunologia Molecolare Alberto Monroy, Consiglio Nazionale delle Ricerche, Palermo, Italy
Giuseppe Montalto
Dipartimento di Medicina Clinica e Patologie Emergenti, Università di Palermo, Palermo, Italy
Melchiorre Cervello
Istituto di Biomedicina e Immunologia Molecolare Alberto Monroy, Consiglio Nazionale delle Ricerche, Palermo, Italy
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.