Antitumor effects of inhibitors of nitric oxide synthase or cyclooxygenase-2 on human KB carcinoma cells overexpressing COX-2.
Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are major inflammatory mediators. Nitric oxide (NO) produced by iNOS has been shown to have an important role in carcinogenesis. Recent studies have suggested that COX-2 expression also contributes to carcinogenesis, as well as tumor growth, invasion, and metastasis. COX-2 inhibitors such as celecoxib are widely recognized to have antitumor activity, but can cause adverse effects. We investigated possible relations between COX-2 and NO with the use of a human epidermoid carcinoma cell line, designated KB, in which overexpression of COX-2 protein was induced by gene transfer. We also assessed the possibility of using NOS inhibitor as an antitumor drug. We isolated a COX-2 transfected clone (KB/COX-2) and used a neomycin-transfected clone (KB/neo) as control. NG-nitro-L-arginine-methyl ester (L-NAME) was used as a NOS inhibitor, dihydrochloride (1400W) as an iNOS inhibitor, and celecoxib as a selective COX-2 inhibitor. All agents inhibited the cell growth of both clones to similar extents in a dose-dependent manner. Prostaglandin E2 (PGE2) production and COX-2 expression in KB/COX-2 were inhibited not only by celecoxib, but also by L-NAME and 1400W. The decreases in PGE2 production and COX-2 expression were most prominent with celecoxib and L-NAME. In vivo, L-NAME and celecoxib significantly inhibited the proliferation of KB/COX-2-xenografted tumors. Tumor weight was reduced by L-NAME (60.6% decrease), 1400W (38.0% decrease), and celecoxib (74.5% decrease) as compared with the control after 21 days of treatment. Immunohistochemically, xenografted tumors expressed COX-2, iNOS, and eNOS. Such expression was suppressed by treatment with L-NAME and celecoxib. These results suggest that L-NAME and celecoxib significantly inhibit the proliferation of murine squamous cell carcinoma in vivo. L-NAME as well as celecoxib might thus be useful for the design and development of new antitumor drugs.
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Nao
N
Ohtsu
Kazuki
K
Takaoka
Emi
E
Segawa
Susumu
S
Hashitani
Kazuma
K
Noguchi
Hiromitsu
H
Kishimoto
Masahiro
M
Urade
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007624:KB Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester