Yoshitake R, Saeki K, Watanabe M, Nakaoka N, Ong S M, Hanafusa M, Choisunirachon N, Fujita N, Nishimura R, Nakagawa T
Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Department of Medical Genome Science, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8561, Japan.
Vet J. 2017 Mar;221:38-47. doi: 10.1016/j.tvjl.2017.02.001. Epub 2017 Feb 3.
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), PGD synthases, and PGE synthases 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.
非甾体抗炎药（NSAIDs）已被认为是人类和兽医学中有效的辅助抗肿瘤药物。然而，与其抗肿瘤作用相关的分子机制以及与肿瘤中环氧合酶（COX）和相关分子表达的相关性仍存在争议。本研究的目的是比较COX和相关分子的表达谱与NSAID敏感性，并探索抗肿瘤作用的分子机制。利用26种犬癌细胞系，获得了COXs、前列腺素（PGs）、PGD合酶和PGE合酶的表达谱，并检测了它们与对NSAIDs吡罗昔康、卡洛芬和罗贝考昔的体外敏感性的相关性。随后，使用一种黑色素瘤细胞系进行微阵列分析，以深入了解NSAIDs发挥细胞毒性作用的机制。未观察到COX和相关分子的细胞表达与NSAID治疗敏感性之间存在强相关性。此外，NSAIDs仅在比功能性COX抑制所需浓度高得多的浓度下才抑制细胞生长。微阵列数据表明，NSAIDs处理黑色素瘤细胞系后，五个基因（SLC16A6、PER2、SLC9A8、HTR2B和BRAF）显著上调，四个基因（LOC488305、H2AFJ、LOC476445和ANKRD43）显著下调。这些结果表明，NSAIDs的直接体外抗肿瘤作用可能由COX/PG非依赖性途径介导。鉴定出了可能参与NSAIDs抗肿瘤作用的新候选基因。对其相关机制的进一步验证和阐明将有助于临床环境中的患者选择和有效联合治疗的开发。
