A cyclooxygenase (cox)-2 inhibitor and ppar-gamma agonist enhances the antitumor effect of docetaxel in lung tumors in mice

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The purpose of this study was to investigate a combination treatment regimen including a COX-2 inhibitor celecoxib, a peroxisome proliferator activated receptor (PPAR)-gamma agonist 15dPGJ₂ and an anticancer agent docetaxel in inhibition of tumor progression in mice bearing s.c human lung adenocarcinoma, A549 tumors. Six-weeks old female athymic nu/nu mice were xenografted with A549 lung tumors by s.c administration of 5x10⁶ A549 cells in the right hind leg. The mice were treated starting day 14 after tumor implantation with vehicle (control), 15dPGJ₂, celecoxib + 15dPGJ₂, docetaxel + 15dPGJ₂ or celecoxib + 15dPGJ₂ + docetaxel. Celecoxib (CXB) was given daily (150 mg/kg/day) by oral gavage, while 15dPGJ₂ (1 mg/kg/day) was given i.p. everyday until the end of the study (28 days). Docetaxel (10 mg/kg) was given by i.v on days 14, 18 and 22 after tumor implantation. Tumor dimensions (longest and shortest diameters) were measured weekly twice and used to compute the tumor volume. The levels of COX-2 and PPAR-gamma, as a result of the combination treatment, were studied by Western Blotting in tumors harvested from mice. Human cancer microarray (Oligo GEArray®) (SuperArray, Frederick, MD) was performed to compare the levels of gene expressions between untreated control and CXB+15dPGJ₂+docetaxel treated tumor samples. Our results indicate that there was 75% inhibition of tumor growth by the combination treatment of celecoxib + 15dPGJ₂ + docetaxel as compared to 63% by 15dPGJ₂+docetaxel, 50% by 15dPGJ₂+CXB and 23% by 15dPGJ₂ alone. All the treatments showed a statistically significant (P<0.0001) inhibition of tumor growth, as compared to the tumor volume of vehicle treated control mice at 28 days. Western Blotting studies showed that there was an enhanced expression of PPAR-gamma in tumors harvested from mice as a result of 15dPGJ₂ alone or in combination with CXB and docetaxel treatments compared to control. There was no change in COX-2 expression as a result of the treatments over the control. A whole array of genes which were implicated in regulation of cell cycle, transcription, cell differentiation, protein stabilization and G protein coupled receptor protein signaling were down regulated as a result of the CXB + 15dPGJ₂ + docetaxel combination treatment. Hence in the present study, although the treatments were initiated two weeks after the tumor implantation when the average tumor volume varied from 400-600 mm², the combination of CXB + 15dPGJ₂ + docetaxel showed significant tumor growth inhibition and regression. These results indicate that it is possible to obtain a superior antitumor effect by the combination of CXB + 15dPGJ₂ + docetaxel in advanced A549 lung tumors.