抗真菌剤ボリコナゾールによる芳香族炭化水素受容体を介した皮膚癌進展機序の解明

阐明抗真菌剂伏立康唑引起的芳香烃受体介导的皮肤癌进展机制

• 批准号: 16K19714
• 负责人: 池谷 茂樹
• 金额: $ 2.41万
• 依托单位: Hamamatsu University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2016
• 资助国家: 日本
• 起止时间: 2016-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16K19714/
• 关键词: ボリコナゾール; 光線性皮膚癌; 芳香族炭化水素受容体; COX-2; 活性酸素; 皮膚癌; 芳香族炭化水素

Voriconazole (VRCZ) induces the development of UV-associated skin cancers. The mechanism underlying the VRCZ-induced carcinogenesis has been largely unknown.Clinical studies (VRCZ-induced skin tumors were clinically summarized, and VRCZ-induced actinic keratosis (AK) were histopathologically compared with ordinary AK) suggested that VRCZ can strongly evoke the tumor formation of keratinocytes (KC)s under a certain immunocompromised condition and its tumorigenesis is not simply caused by photosensitivity. In vitro, we showed that VRCZ metabolites plus UVA generated reactive oxygen species and resultant DNA damage of the epidermis, but did not induce substantial apoptosis in KCs. Furthermore, VRCZ per se stimulates aryl hydrocarbon receptor (AhR) and upregulates COX-2, which is a pivotal enzyme for the promotion of UV-associated tumors, in an AhR-ARNT dependent manner of the classical (genomic) pathway.Our findings suggest that VRCZ primarily promotes the tumor development of preexisted UV-damaged KCs in clinical settings, while the phototoxic moieties of VRCZ metabolites may participate in the initiation phase.

伏立康唑(VRCZ)会导致紫外线相关皮肤癌的发生。VRCZ诱发皮肤肿瘤的临床研究和光化性角化病(AK)与普通AK的组织病理学比较表明，在一定的免疫抑制条件下，VRCZ能强烈地诱导S角质形成细胞(KC)的肿瘤形成，其肿瘤发生不是简单的光敏作用所致。在体外，我们发现VRCZ代谢物加UVA能产生活性氧，并导致表皮DNA损伤，但不能诱导KCs实质上的凋亡。此外，VRCZ本身刺激芳香烃受体(AhR)并上调COX-2，COX-2是促进紫外线相关肿瘤的关键酶，其依赖于AhR-Arnt的经典(基因组)途径。我们的研究结果表明，VRCZ在临床上主要促进先前存在的紫外线损伤的KCs的肿瘤发展，而VRCZ代谢物的光毒部分可能参与了启动阶段。

项目成果

抗真菌剤ボリコナゾール投与中に生じた光線角化症とその発症機序の検討

抗真菌药伏立康唑用药过程中发生的光化性角化病及其发病机制的研究

• 发表时间: 2016
• 作者: Daisuke Ieda;Ikumi Hori;Yuji Nakamura;Hironori Ohshita;Yutaka Negishi Tsutomu Shinohara;Ayako Hattori;Takenori Kato;Sachiko Inukai Katsumasa Kitamura;Shinji Kunishima;Tomoki Kawai;Osamu Ohara;Shinji Saitoh;池谷茂樹
• 通讯作者: 池谷茂樹