Etodolac, a selective cyclooxygenase-2 inhibitor, inhibits liver metastasis of colorectal cancer cells via the suppression of MMP-9 activity.
Synchronous or metachronous liver metastasis occurs in approximately 15% of colorectal cancer patients and is an important negative prognostic factor. We therefore need an effective therapy to prevent metastasis. It has become apparent that cyclooxygenase (COX)-2 plays an important role in cancer growth, invasion and metastasis and that there is potential for chemoprevention via inhibition of these processes. We injected colon 26, a colorectal cancer cell line, in CDF1 mouse spleen and, from the following day, two kinds of COX-2 inhibitor (etodolac and nimesulide) were administered orally. Two weeks later, the animals were sacrificed, the liver was excised, and we counted the number of metastatic nodules on the liver surface. In addition, COX-2 mRNA, matrix metalloproteinase (MMP)-9 mRNA, and tissue inhibitor of MMP (TIMP)-1 mRNA of cancer tissue were measured by means of real-time RT-PCR. The number of metastatic nodules on the liver surface was significantly lower in the etodolac-treated group than in controls (p=0.001), but no significant difference was noted in the nimesulide-treated group. The expression of COX-2 mRNA was also significantly lower in the etodolac-treated group than in controls (p=0.04), but not in the nimesulide-treated group. In addition, the expression of MMP-9 mRNA was significantly lower in the etodolac group than in controls (p=0.02), but not in the nimesulide group. Among the groups, there were no significant differences in TIMP-1 mRNA. Expression of COX-2 mRNA and MMP-9 mRNA correlated significantly (r=0.78, p=0.001), but there was no correlation between either COX-2 mRNA and TIMP-1 mRNA expression or between MMP-9 mRNA and TIMP-1 mRNA expression. These findings indicate that the selective COX-2 inhibitor, etodolac, suppresses liver metastasis by reducing MMP-9 activity.
Ishizaki
Tetsuo
T
Third Department of Surgery, Tokyo Medical University, Tokyo, Japan.
Katsumata
Kenji
K
Tsuchida
Akihiko
A
Wada
Tatehiko
T
Mori
Yasuharu
Y
Hisada
Masayuki
M
Kawakita
Hideaki
H
Aoki
Tatsuya
T
D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D017308:Etodolac / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D013379:Substrate Specificity; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D017308:Etodolac; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9