title: Molecular investigation of the direct anti-tumour effects of nonsteroidal anti-inflammatory drugs in a panel of canine cancer cell lines.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested as effective adjunctive anti-tumour agents in human and veterinary medicine. However, the molecular mechanisms associated with their anti-tumour effects and correlations with the expression of cyclooxygenase (COX) and related molecules in tumours remain controversial. The objective of this study was to compare the expression profiles of COX and related molecules with NSAID sensitivity and to explore the molecular mechanisms of anti-tumour effects. The expression profiles of COXs, prostaglandins (PGs), PGD2synthases, and PGE2synthases were obtained, and their correlations with in vitro sensitivity to the NSAIDs piroxicam, carprofen, and robenacoxib were examined, using 26 canine cancer cell lines. Subsequently, microarray analysis was performed using one melanoma cell line to gain insight into mechanisms by which NSAIDs could exert cytotoxic effects. No strong correlation was observed between the cellular expression of COX and related molecules and sensitivity to NSAID treatment. Additionally, NSAIDs inhibited cell growth only at considerably higher concentrations than those required for functional COX inhibition. Microarray data demonstrated that five genes (SLC16A6, PER2, SLC9A8, HTR2B, and BRAF) were significantly upregulated and that four genes (LOC488305, H2AFJ, LOC476445, and ANKRD43) were significantly downregulated by NSAID exposure to the melanoma cell line. These results suggest that the direct in vitro anti-tumour effects of NSAIDs might be mediated by COX/PG-independent pathways. Novel candidate genes that could potentially be involved in the anti-tumour effects of NSAIDs were identified. Further validation and elucidation of their associated mechanisms will contribute to patient selection in clinical settings and the development of effective combination therapies.
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yoshitake
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Department of Medical Genome Science, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8561, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nakaoka
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: S M
authors.initials: SM
authors.lastname: Ong
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hanafusa
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Choisunirachon
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nishimura
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. Electronic address: anakaga@mail.ecc.u-tokyo.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000662:veterinary; D009369:Neoplasms / Q000188:drug therapy / Q000662:veterinary*; D010648:Phenylacetates / Q000627:therapeutic use; D010894:Piroxicam / Q000627:therapeutic use; D015230:Prostaglandin D2 / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D010648:Phenylacetates; D010894:Piroxicam; D004159:Diphenylamine; C007005:carprofen; D015232:Dinoprostone; D015230:Prostaglandin D2; C551524:robenacoxib
keywords: Cancer; Cyclooxygenase; Nonsteroidal anti-inflammatory drug; Prostaglandin; Transcriptome analysis