Itraconazole Increases Resolvin E3 Concentration and 12/15-lipoxygenase Inhibitor Attenuates Itraconazole Cytotoxicity in Cervical Cancer Cells
Itraconazole Increases Resolvin E3 Concentration and 12/15-lipoxygenase Inhibitor Attenuates Itraconazole Cytotoxicity in Cervical Cancer Cells
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DOI：
10.21873/anticanres.15231
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发表时间：
2021-09-01
影响因子：
2
通讯作者：
Shibahara, Hiroaki
中科院分区：
文献类型：
--
作者：
Isono, Roze;Tsubamoto, Hiroshi;Shibahara, Hiroaki
背景/目的：伊曲康唑的抗癌机制仍未解决，因此，我们研究了伊曲康唑诱导的癌细胞中专门的促消退介质（SPM）的改变。材料与方法：人宫颈鳞癌细胞系CaSki在体外培养时，加入或不加入1 μ M伊曲康唑。进行液相色谱/质谱分析以鉴定受伊曲康唑影响的SPM。使用伊曲康唑和靶向候选SPM的代谢途径的抑制剂进行细胞生长实验。结果：分离到5种SPMs，分别为Resolvin E3、Resolvin E2、前列腺素J2（PGJ 2）、delta-12-PGJ 2和maresin 2。12/15-脂氧合酶抑制剂参与18-羟基-二十碳五烯酸转化为消退素E3，减弱了伊曲康唑的抑制作用。PGJ 2代谢途径的抑制不会干扰伊曲康唑治疗。结论：包括E3分解在内的SPM代谢途径可作为伊曲康唑的抗癌靶点。
Background/Aim: The anticancer mechanism of itraconazole remains unsolved; therefore, we studied itraconazole-induced alterations in specialized pro-resolving mediators (SPMs) in cancer cells. Materials and Methods: The human cervical squamous carcinoma cell line CaSki was cultured with or without 1 mu M itraconazole. Liquid chromatography/mass spectrometry analysis was conducted to identify SPMs that were influenced by itraconazole. Cell growth experiments were conducted using itraconazole and inhibitors targeting the metabolic pathways of candidate SPMs. Results: Resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were identified as candidate SPMs. The 12/15-lipoxygenase inhibitor, which is involved in the conversion of 18-hydroxy-eicosapentaenoic acid to resolvin E3, attenuated the inhibitory effect of itraconazole. Inhibition of the PGJ2 metabolic pathway did not interfere with itraconazole treatment. Conclusion: The metabolic pathway of SPMs, including resolving E3, could be proposed as an anticancer target of itraconazole.