Department of Pharmaceutical Science & Technology, College of Chemistry and Biology, Donghua University, Shanghai 201620, China.
Bioorg Med Chem. 2010 Sep 1;18(17):6282-91. doi: 10.1016/j.bmc.2010.07.027. Epub 2010 Jul 16.
Photodynamic therapy (PDT) represents a promising method for treatment of cancerous tumors. The chemical and physical properties of used photosensitizer play key roles in the treatment efficacy. In this study, a novel photosensitizer, Chlorin-H [-13,15-N-(cyclohexyl)cycloimide] which displayed a characteristic long wavelength absorption peak at 698nm was synthesized. Following flash photolysis with 355nm laser, Chlorin-H is potent to react with O(2) and then produce (1)O(2). This finding indicates that Chlorin-H takes its effects through type II mechanism in PDT. Generally, Chlorin-H is localized in mitochondria and nucleus of cell. After light irradiation with 698nm laser, it can kill many types of cell, inhibit cell proliferation and colony formation, suppress cancer cell invasiveness and trigger apoptosis via the mitochondrial pathway in A549 cells in vitro. In addition, Chlorin-H-PDT can destroy A549 tumor in nude mice and a necrotic scab was formed eventually. The expression levels of many genes which regulated cell growth and apoptosis were determined by RT-PCR following Chlorin-H-PDT. The results showed that it either increased or decrease. Among which, the expression level of TNFSF13, a member of tumor necrosis factor superfamily, increased significantly. Silencing of TNFSF13 caused by RNA interference decreased the susceptibility of A549 cells to Chlorin-H-PDT. In general, Chlorin-H is an effective antitumor photosensitizer in vitro and in vivo and is worthy of further study as a new drug candidate. TNFSF13 will be an important molecular target for the discovery of new photosensitizers.
光动力疗法（PDT）是治疗癌症肿瘤的一种很有前途的方法。所用光敏剂的化学和物理性质在治疗效果中起着关键作用。在这项研究中，合成了一种新型光敏剂，即 Chlorin-H [-13,15-N-（环己基）环脒]，其在 698nm 处显示出特征性的长波长吸收峰。用 355nm 激光进行闪光光解后，Chlorin-H 能够与 O(2)强烈反应，然后产生（1）O(2)。这一发现表明 Chlorin-H 在 PDT 中通过 II 型机制发挥作用。一般来说，Chlorin-H 定位于细胞的线粒体和核内。用 698nm 激光照射后，它可以杀死多种类型的细胞，抑制细胞增殖和集落形成，抑制癌细胞侵袭，并通过线粒体途径在体外的 A549 细胞中引发细胞凋亡。此外，Chlorin-H-PDT 可以破坏裸鼠中的 A549 肿瘤，最终形成坏死痂。用 RT-PCR 测定 Chlorin-H-PDT 后，许多调节细胞生长和凋亡的基因的表达水平发生了变化。结果表明，这些基因的表达水平要么增加，要么减少。其中，肿瘤坏死因子超家族成员 TNFSF13 的表达水平显著增加。RNA 干扰沉默 TNFSF13 会降低 A549 细胞对 Chlorin-H-PDT 的敏感性。总之，Chlorin-H 是一种有效的体外和体内抗肿瘤光敏剂，值得进一步研究作为一种新的药物候选物。TNFSF13 将成为发现新光敏剂的重要分子靶标。
