Inhibitory effect of sulindac on DMBA-induced hamster cheek pouch carcinogenesis and its derived cell line.
In order to investigate the involvement of cyclooxygenase (COX)-2 in oral carcinogenesis and chemoprevention for it, we examined the COX-2 expression during dimethylbenzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis and the inhibitory effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID), on the carcinogenesis and its derived squamous carcinoma cell line HCPC-1. From the beginning of DMBA application, basal diet or diets containing sulindac 200 or 400 ppm were given to hamsters, and observation of tumor development and measurement of body weight were performed. Immunohistochemical analysis revealed that COX-2 expression was increased toward carcinogenesis from epithelial dysplasia to squamous cell carcinoma (SCC). All hamsters developed SCC, but the onset of carcinoma formation was significantly delayed up to 14.8 and 11.8 weeks in the 200 ppm, and 400 ppm sulindac group, respectively, as compared to 8.7 weeks in the control group. In addition, tumor growth was retarded in the group of sulindac treatment, and mean survival time was 23.7 weeks in the control group and 36.3 and 33.8 weeks in the 200 and 400 ppm sulindac group, respectively. Body weight loss was not observed during the experimental period. Histologically, administration of sulindac inhibited angiogenesis in the tumor stroma. Treatment with sulindac sulfide, an active metabolite of sulindac, caused inhibition of cell growth, PGE2 production and VEGF production in HCPC-1 cells in vitro. Expression of COX-2 protein in HCPC-1 cells was also decreased 2-fold by treatment with sulindac sulfide. It was thus indicated that inhibitory effects were partly due to inhibition of tumor angiogenesis by sulindac. These findings suggested the involvement of COX-2 in DMBA-induced hamster cheek pouch carcinogenesis and the chemopreventive potential of sulindac.
Segawa
Emi
E
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan.
Hashitani
Susumu
S
Toyohara
Yukiyo
Y
Kishimoto
Hiromitsu
H
Noguchi
Kazuma
K
Takaoka
Kazuki
K
Urade
Masahiro
M
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002610:Cheek; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000032:analysis; D015232:Dinoprostone / Q000096:biosynthesis; D008297:Male; D008647:Mesocricetus; D009061:Mouth Mucosa; D009062:Mouth Neoplasms / Q000098:blood supply / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013467:Sulindac / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D042461:Vascular Endothelial Growth Factor A; D013467:Sulindac; D015127:9,10-Dimethyl-1,2-benzanthracene; D051546:Cyclooxygenase 2; D015232:Dinoprostone