期刊
INTERNATIONAL JOURNAL OF CANCER
卷 118, 期 2, 页码 396-404出版社
WILEY
DOI: 10.1002/ijc.21325
关键词
COX-2; A549; PPAR-gamma; PGE(2)
类别
资金
- NCRR NIH HHS [G12 RR003020, G12 RR003020-255369, G12 RR003020-200011] Funding Source: Medline
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 E-2 (PGE(2)), 15 deoxy prostaglandin J(2) (15-d PGJ(2)), microsomal prostaglandin E synthase (mPGES) and cytoplasmic phospholipase A(2) (cPLA(2)). 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 cPLA(2,) 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 PGE(2) and 15-d PGJ(2) (c) 2005 Wiley-Liss, Inc.
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