Suppression by apigenin of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats.
The effect of a naturally occurring flavonoid apigenin on the development of bombesin-enhanced peritoneal metastasis from intestinal adenocarcinomas induced by azoxymethane was investigated in male Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of azoxymethane (7.4 mg/kg body weight) for 10 weeks and s.c. injection of bombesin (40 microg/kg body weight) every other day, and from week 16, s.c. injections of apigenin (0.75 or 1.5 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of apigenin at either dose with bombesin had little or no effect on the enhancement of intestinal carcinogenesis by bombesin, the location, histologic type, depth of involvement, infiltrating growth patterns and labeling index, it was found to decrease significantly the incidence of cancer metastasis. Apigenin significantly decreased the incidence of lymphatic vessel invasion of adenocarcinomas, which was enhanced by bombesin. In vitro experiments revealed that apigenin inhibited bombesin-enhanced phosphorylation of mitogen-activated protein kinase (MAPK), but not matrix metalloprotease (MMP)-9 expression. Our findings indicate that apigenin inhibits cancer metastasis through inhibition of phosphorylation of MAPK.
Tatsuta
A
A
Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.
Iishi
H
H
Baba
M
M
Yano
H
H
Murata
K
K
Mukai
M
M
Akedo
H
H
D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047310:Apigenin; D001397:Azoxymethane / Q000633:toxicity; D001839:Bombesin / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D005419:Flavonoids / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000556:secondary; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D002273:Carcinogens; D005419:Flavonoids; D018809:Proliferating Cell Nuclear Antigen; D047310:Apigenin; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9; D001397:Azoxymethane; D001839:Bombesin