Enhancement of antitumor activity of docetaxel by celecoxib in lung tumors.
Our study investigates the effect of a highly selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the cytotoxicity of docetaxel in nude mice bearing A549 tumor xenografts and elucidates the molecular mechanisms of the antitumor effect of this combination. Female nu/nu mice, xenografted with s.c. A549 tumors were treated with either celecoxib (150 mg/kg/day), docetaxel (10 mg/kg) or a combination of both. The tumor tissues were quantified for the induction of apoptosis, intratumor levels/expressions of prostaglandin E2 (PGE2), 15 deoxy prostaglandin J2 (15-d PGJ2), microsomal prostaglandin E synthase (mPGES) and cytoplasmic phospholipase A2 (cPLA2). The combination of celecoxib with docetaxel significantly inhibited the tumor growth (p < 0.03) as compared to celecoxib or docetaxel alone, decreased the levels of PGE2 by 10-fold and increased the 15-d PGJ2 levels by 4-fold as compared to control. The combination also enhanced the peroxisome proliferator-activated receptor (PPAR)-gamma expression, decreased the expression of cPLA2, mPGES and vascular endothelial growth factor (VEGF), but had no effect on the expression of COX-1 or COX-2 in tumor tissues. TUNEL staining of the tumor tissues showed a marked increase in the apoptosis in the combination group as compared to the celecoxib- or docetaxel-treated groups and this was associated with an increase in the intratumor p53 expression. In conclusion, the combination of celecoxib with docetaxel produces a greater antitumor effect in s.c. A549 tumors as compared to celecoxib or docetaxel alone and this effect is associated with concomitant alterations in the intratumor levels of PGE2 and 15-d PGJ2.
Shaik
Madhu Sudhan
MS
College of Pharmacy, Florida A&M University, Tallahassee, FL 32307, USA.
Chatterjee
Abhijit
A
Jackson
Tanise
T
Singh
Mandip
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D015232:Dinoprostone / Q000096:biosynthesis; D004347:Drug Interactions; D005260:Female; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D015232:Dinoprostone