Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes
Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes
复制标题
Ibudilast 通过抑制 TRPC3 通道和 NADPH 氧化酶 2 蛋白复合物的形成来减弱阿霉素诱导的细胞毒性
DOI：
10.1111/bph.14777
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发表时间：
2019
影响因子：
7.3
通讯作者：
Nishida Motohiro
中科院分区：
文献类型：
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作者：
Nishiyama Kazuhiro;Numaga‐Tomita Takuro;Fujimoto Yasuyuki;Tanaka Tomohiro;Toyama Chiemi;Nishimura Akiyuki;Yamashita Tomohiro;Matsunaga Naoya;Koyanagi Satoru;Azuma Yasu‐Taka;Ibuki Yuko;Uchida Koji;Ohdo Shigehiro;Nishida Motohiro
背景和目的阿霉素是一种高效的抗癌药物，但最终会导致与ROS产生增加相关的心脏毒性。我们先前报道了TRPC3通道和NADPH氧化酶2(NOX2)之间的病理性蛋白质相互作用导致了阿霉素诱导的小鼠心肌萎缩。在这里，我们研究了异丁司特对TRPC3-NOX2复合体的影响。异丁司特是一种已被批准临床使用的药物，已知可以阻断阿霉素诱导的细胞毒性。实验方法我们使用RAW264.7巨噬细胞系筛选了1,271个临床批准的化合物，通过测量NOX2蛋白稳定性和ROS产生来评估TRPC3通道和NOX2之间的功能相互作用，在有和没有接触阿霉素的情况下。取雄性C57BL/6小鼠心脏和腓肠肌标本，采用形态计量学、免疫组织化学、RT-PCR和免疫印迹等方法进行分析。在被动吸烟模型中，细胞暴露于含有香烟侧流烟雾的DMEM。关键结果抗哮喘药物异丁司特通过抑制TRPC3通道与NOX2之间的功能相互作用，而不降低TRPC3通道的活性，减轻阿霉素或被动吸烟引起的ROS介导的肌肉毒性。结论与意义这些结果表明阿霉素诱导全身组织损耗的共同机制。他们还建议可以改变异丁司特的用途，以防止抗癌药物或被动吸烟引起的肌肉毒性。
Background and PurposeDoxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin‐induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin‐induced cytotoxicity, on the TRPC3‐Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin‐induced systemic tissue wasting in mice.Experimental ApproachWe used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT‐PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke.Key ResultsIbudilast, an anti‐asthmatic drug, attenuated ROS‐mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity.Conclusions and ImplicationsThese results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.