COX-2 inhibitor celecoxib suppresses tumor growth and lung metastasis of a murine mammary cancer.
BACKGROUND
The antitumor growth and antimetastatic actions of celecoxib [a selective cyclooxygenase-2 (COX-2) inhibitor] were investigated in a metastatic murine mammary cancer model.


METHODS
Mice bearing mammary tumors, developed after inoculation of syngeneic BALBIc mice with a mammary carcinoma cell line carrying a p53 mutation, were treated with celecoxib at 0, 7.5 and 15 mg/kg five times a week for seven weeks.


RESULTS
Tumor volumes were significantly reduced in association with an increase in apoptosis and a decrease in DNA synthesis in tumor tissues. In vitro studies demonstrated a significant increase in the number of cells undergoing apoptosis, with significantly elevated activities of caspase-3 and caspase-9, but not caspase-8, and a dose-dependent decrease in mitochondrial membrane potential, indicating the mitochondrial pathway of apoptosis. In addition, treatment with celecoxib showed cell cycle arrest in the G -phase and decreased cell population in the S- and G2/M-phases. Furthermore, tumor microvessel formation and mRNA levels for VEGF-A and COX-2 were markedly decreased.


CONCLUSIONS
Celecoxib may be useful as an adjuvant therapy for breast cancer containing p53 mutations due to its ability to both induce p53-independent mitochondria-mediated apoptosis and exert anti-angiogenic potential.
Yoshinaka
Ryoji
R
Department of Anatomy and Cell Biology, Division of Basic Medicine I, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
Shibata
Masa-Aki
MA
Morimoto
Junji
J
Tanigawa
Nobuhiko
N
Otsuki
Yoshinori
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib