Cancer phototherapy via selective photoinactivation of respiratory chain oxidase to trigger a fatal superoxide anion burst.
Cancer phototherapy via selective photoinactivation of respiratory chain oxidase to trigger a fatal superoxide anion burst.
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DOI：
10.1089/ars.2013.5229
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发表时间：
2014-01
影响因子：
6.6
通讯作者：
Sheng-nan Wu;Feifan Zhou;Yanchun Wei;Wei R. Chen;Qun Chen;D. Xing
中科院分区：
文献类型：
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作者：
Sheng-nan Wu;Feifan Zhou;Yanchun Wei;Wei R. Chen;Qun Chen;D. Xing
本研究旨在探索线粒体靶向、高能量、低功率激光照射(HF-LPLI)治疗小鼠肿瘤的新方法，并探讨HF-LPLI损伤线粒体的机制。结果光子吸收后的初始反应是细胞色素c氧化酶(COX)的光敏化，在原位抑制COX的活性，引起呼吸链超氧阴离子(O2-·)的爆发。我们还发现HF-LPLI通过电子传递链(ETC)通过线粒体O2(-·)爆发发挥其主要的肿瘤杀伤作用。这些现象在呼吸缺陷细胞和COX基因敲除细胞中完全不存在。通过精心选择的照射方案，HF-LPLI可以有效地摧毁肿瘤。体内实验还检测了HF-LPLI对COX酶活性和O2(-·)生成的抑制作用。首次阐明了HF-LPLI处理下光与其受光体相互作用的机制。我们的结果清楚地表明，HF-LPLI通过靶向COX光灭活来启动其作用，其杀瘤效果依赖于随后通过ETC的线粒体O2(-·)爆发。结论体外和体内实验结果表明，HF-LPLI可以选择性地光灭活呼吸链氧化酶，触发致死性线粒体O2(-·)爆发，对癌细胞产生氧化损伤。这项研究为HF-LPLI作为线粒体靶向癌症光疗的应用开辟了可能性。
AIMS Here, we develop a novel cancer treatment modality using mitochondria-targeting, high-fluence, low-power laser irradiation (HF-LPLI) in mouse tumor models and explore the mechanism of mitochondrial injury by HF-LPLI. RESULTS We demonstrated that the initial reaction after photon absorption was photosensitization of cytochrome c oxidase (COX), to inhibit enzymatic activity of COX in situ and cause respiratory chain superoxide anion (O2(-•)) burst. We also found that HF-LPLI exerted its main tumor killing effect through mitochondrial O2(-•) burst via electron transport chain (ETC). These phenomena were completely absent in the respiration-deficient cells and COX knockdown cells. With a carefully selected irradiation protocol, HF-LPLI could efficaciously destroy tumors. The inhibition of enzymatic activity of COX and generation of O2(-•) by HF-LPLI in vivo were also detected. INNOVATION It is the first time that the mechanism involved in the interaction between light and its photoacceptor under HF-LPLI treatment is clarified. Our results clearly indicate that HF-LPLI initiates its effects via targeted COX photoinactivation and that the tumor-killing efficacy is dependent of the subsequent mitochondrial O2(-•) burst via ETC. CONCLUSION Based on both in vitro and in vivo results, we conclude that HF-LPLI can selectively photoinactivate respiratory chain oxidase to trigger a fatal mitochondrial O2(-•) burst, producing oxidative damage on cancer cells. This study opens up the possibilities of applications of HF-LPLI as a mitochondria-targeting cancer phototherapy.