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.
Ohtsu
Nao
N
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Takaoka
Kazuki
K
Segawa
Emi
E
Hashitani
Susumu
S
Noguchi
Kazuma
K
Kishimoto
Hiromitsu
H
Urade
Masahiro
M
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