Celecoxib inhibits tumor growth and angiogenesis in an orthotopic implantation tumor model of human colon cancer.
OBJECTIVE
To examine the effect of celecoxib on tumor growth and angiogenesis in an orthotopic implantation tumor model of colon cancer.


METHODS
Human colorectal adenocarcinoma HT-29 cells were implanted subcutaneously in nude mice. Four groups of animals received different doses of celecoxib after tumor implantation. After 42 days, all animals were evaluated for changes in body weight, the volume and weight of colorectal tumors, and tumor growth inhibition. The content of prostaglandin E(2) (PGE(2)) in the tumor tissue homogenate was estimated by radioimmunoassay (RIA). Cyclooxygenase-2 (COX-2) and CD34 expression in tumor tissue was assessed by immunohistochemistry, and the microvessel density (MVD) of tumor tissue was determined. Apoptosis of the tumor cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). The expression of vascular endothelial growth factor (VEGF) mRNA and matrix metalloproteinase-2 (MMP-2) mRNA extracted from the tumor tissue was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR).


RESULTS
There was no statistically significant change in the animals' body weight between the treatment groups. However, with increasing doses of celecoxib, the volume and weight of the tumor decreased. The rates of tumor growth inhibition for the L (low), M (medium) and H (high) groups were 25.30%, 38.80%, and 76.92%, respectively, which were significant compared to the C (control) group. There were significant differences in COX-2 expression in the tumor tissue between all groups, except between the L and M groups. Celecoxib exposure also reduced PGE2 levels in the tumor tissue homogenates. The level of PGE(2) correlated to the weight of tumor (r=0.8814, P < 0.05) and to COX-2 expression (r=0.8249, Puse < 0.05). Compared to the control group, the tumor cells from celecoxib-treated mice had a significantly higher apoptotic index. Celecoxib also decreased CD34(+) expression in tumors from treated mice. There were significant differences in the MVD between all groups except between groups H and M. Celecoxib significantly reduced the expression of VEGF and MMP-2 mRNA in the group H but not in L and M groups. The MVD in tumor tissue was closely related to the PGE2 levels, as well as the expression of VEGF and MMP-2 mRNA (r = 0.9006, r = 0.8573 and r = 0.6427, respectively; P < 0.05).


CONCLUSIONS
By inhibiting COX-2, PGE(2) synthesis, and VEGF and MMP-2 mRNA expression in tumor tissue, celecoxib enhances tumor cell apoptosis, thereby inhibiting the growth and angiogenesis of orthotopically implanted tumors in a mouse model of human colorectal cancer.
Wang
L
L
Department of Gastroenterology, the First Affiliated Hospital of Soochow University, Jiangsu, China.
Chen
W
W
Xie
X
X
He
Y
Y
Bai
X
X
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; D000068579:Celecoxib; D015232:Dinoprostone