Department of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China.
Department of Chemistry, Key Laboratory of Functional Molecular Engineering of Guangdong Province, South China University of Technology, Guangzhou, 510640, People's Republic of China.
Lasers Med Sci. 2019 Sep;34(7):1353-1363. doi: 10.1007/s10103-019-02725-4. Epub 2019 Feb 2.
Corrole is a kind of new and promising photosensitizer (PS) in cancer photodynamic therapy (PDT). However, the protein molecular mechanism of PDT activity for corrole under light irradiation is still not clear. In this paper, water-soluble cationic sulfonated corrole (1) and its metal complexes (1-Fe, 1-Mn, and 1-Cu) were prepared, and the photodynamic anti-cancer activity against various tumor cells was investigated by MTT assay. The potential molecular mechanism of PDT activity was elucidated by fluorescence microscope, flow cytometry, molecular docking, and western blotting analysis. Besides, the potential PDT anti-tumor effect of 1 in vivo was assessed in human tumor xenografts in mice. Quantitative analysis revealed that 1's phototoxicity triggered a significant generation of reactive oxygen species, causing disruption of mitochondrial membrane potential. The results of western blotting (WB) assay shown in 1's phototoxicity could induce cell apoptosis via ROS-mediated mitochondrial caspase apoptosis pathway, in which SIRT1 protein degradation played a key role. PTD activity in vivo shown in 1 could significantly reduce the growth of A549 xenografted tumor, without obvious loss of mice body weight. We clearly found that cationic sulfonated corrole is a potential candidate of PS in vitro and in vivo. The phototoxicity of 1 could induce A549 cell apoptosis by inducing ROS production increase, further to activate the mitochondrial apoptosis pathway. We concluded that SIRT1 protein is a more appropriate target in this progress.
卟啉是一种新型、有前途的用于癌症光动力治疗（PDT）的光敏剂（PS）。然而，在光照下，卟啉 PDT 活性的蛋白质分子机制尚不清楚。本文制备了水溶性阳离子磺化卟啉（1）及其金属配合物（1-Fe、1-Mn 和 1-Cu），并通过 MTT 法测定了它们对各种肿瘤细胞的光动力抗癌活性。通过荧光显微镜、流式细胞术、分子对接和 Western blot 分析阐明了 PDT 活性的潜在分子机制。此外，还在荷人肿瘤的小鼠体内评估了 1 的潜在 PDT 抗肿瘤作用。定量分析显示，1 的光毒性引发了大量活性氧的产生，导致线粒体膜电位破坏。Western blot（WB）检测结果显示，1 的光毒性通过 ROS 介导的线粒体 caspase 凋亡途径诱导细胞凋亡，其中 SIRT1 蛋白降解起关键作用。体内 PDT 活性显示，1 可显著抑制 A549 异种移植瘤的生长，而小鼠体重无明显下降。我们清楚地发现，阳离子磺化卟啉是体外和体内 PS 的潜在候选物。1 的光毒性通过诱导 ROS 生成增加诱导 A549 细胞凋亡，进而激活线粒体凋亡途径。我们得出结论，SIRT1 蛋白是这一过程中更合适的靶标。
