Synergistic effect of gefitinib and rofecoxib in mesothelioma cells.
BACKGROUND
Malignant mesothelioma (MM) is an aggressive tumor that is resistant to conventional modes of treatment with chemotherapy, surgery or radiation. Research into the molecular pathways involved in the development of MM should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of MM. Combination of COX-2 and EGFR inhibitors, therefore, could be an effective strategy for reducing cell growth in those lines expressing the two molecular markers.


RESULTS
In order to verify the effect of COX-2 and EGFR inhibitors, five MM cell lines NCI-2452, MPP89, Ist-Mes-1, Ist-Mes-2 and MSTO-211 were characterized for COX-2 and EGFR and then treated with respective inhibitors (rofecoxib and gefitinib) alone and in combination. Only MPP89, Ist-Mes-1 and Ist-Mes-2 were sensitive to rofecoxib and showed growth-inhibition upon gefitinib treatment. The combination of two drugs demonstrated synergistic effects on cell killing only in Ist-Mes-2, the cell line that was more sensitive to gefitinib and rofecoxib alone. Down-regulation of COX-2, EGFR, p-EGFR and up-regulation of p21 and p27 were found in Ist-Mes-2, after treatment with single agents and in combination. In contrast, association of two drugs resulted in antagonistic effect in Ist-Mes-1 and MPP89. In these cell lines after rofecoxib exposition, only an evident reduction of p-AKT was observed. No change in p-AKT in Ist-Mes-1 and MPP89 was observed after treatment with gefitinib alone and in combination with rofecoxib.


CONCLUSIONS
Gefitinib and rofecoxib exert cell type-specific effects that vary between different MM cells. Total EGFR expression and downstream signalling does not correlate with gefitinib sensitivity. These data suggest that the effect of gefitinib can be potentiated by rofecoxib in MM cell lines where AKT is not activated.
Stoppoloni
Daniela
D
Department for the Development of Therapeutic Programs, Laboratory D, Centro Ricerca Sperimentale, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, 00158 Rome, Italy.
Canino
Claudia
C
Cardillo
Irene
I
Verdina
Alessandra
A
Baldi
Alfonso
A
Sacchi
Ada
A
Galati
Rossella
R
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008654:Mesothelioma / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D007783:Lactones; D011799:Quinazolines; D013450:Sulfones; C116926:rofecoxib; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib