A Novel Photodynamic Therapy Targeting Cancer Cells and Tumor-Associated Macrophages
A Novel Photodynamic Therapy Targeting Cancer Cells and Tumor-Associated Macrophages
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DOI：
10.1158/1535-7163.mct-14-0348
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发表时间：
2015-02-01
影响因子：
5.7
通讯作者：
Joh, Takashi
中科院分区：
文献类型：
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作者：
Hayashi, Noriyuki;Kataoka, Hiromi;Joh, Takashi
肿瘤基质中的肿瘤相关巨噬细胞（tumor associated macrophages， TAM）在癌细胞生长、侵袭、血管生成和转移中起着重要作用。我们合成了一种新的光敏剂，甘露糖共轭氯（m -氯），旨在结合在tam上高度表达的甘露糖受体。我们评估了最新的光动力疗法（PDT）与m -氯治疗胃癌和结肠癌。与单独使用氯和葡萄糖偶联氯（g -氯）相比，我们评估了Mchlorin联合PDT对癌细胞的体外细胞毒性和诱导凋亡的作用。通过共聚焦显微镜观察M-chlorin的亚细胞定位，并评估M-chlorin对包括thp -1诱导的m2极化巨噬细胞在内的tam的PDT作用。在同种异体移植模型中也研究了抗癌作用，通过免疫组织化学分析了对癌细胞基质中tam的细胞毒性作用。M-chlorin PDT通过诱导细胞凋亡而强烈诱导癌细胞死亡，其程度与G-chlorin PDT几乎相同。间氯被纳入癌细胞，主要定位于溶酶体和内质网。M-chlorin PDT对THP-1细胞系诱导的M2巨噬细胞显示出较强的细胞毒性，在同种异体移植模型中，M-chlorin PDT通过杀死癌细胞和癌基质中的tam而诱导的细胞毒性强于G-chlorin PDT。间氯林PDT通过诱导癌细胞和癌间质tam的凋亡，对癌组织产生较强的细胞毒性。这种新颖的PDT因此成为非常有效的新一代PDT的新候选。(c) 2014年aacr。
Tumor-associated macrophages (TAM) in cancer stroma play important roles for cancer cell growth, invasion, angiogenesis, and metastases. We synthesized a novel photosensitizer, mannose-conjugated chlorin (M-chlorin), designed to bind mannose receptors highly expressed on TAMs. We evaluated the newly available photodynamic therapy (PDT) with M-chlorin against gastric and colon cancer. We evaluated PDT with Mchlorin for in vitro cytotoxicity and apoptosis induction in cancer cells compared with chlorin alone and glucose-conjugated chlorin (G-chlorin). The subcellular localization of M-chlorin was observed by confocal microscopy, and the M-chlorin PDT effects against TAMs including THP-1-induced M2-polarized macrophages were evaluated. Anticancer effects were also investigated in an allograft model where cytotoxic effects against TAMs in the cancer cell stroma were analyzed by immunohistochemistry. M-chlorin PDT strongly induced cell death in cancer cells to almost the same extent as G-chlorin PDT by inducing apoptosis. M-chlorin was incorporated into cancer cells where it localized mainly in lysosomes and endoplasmic reticula. M-chlorin PDT revealed strong cytotoxicity for M2 macrophages induced from THP-1 cell lines, and it induced stronger cytotoxicity than G-chlorin PDT in the allograft model through killing both cancer cells and TAMs in the cancer stroma. The M-chlorin PDT produced strong cytotoxicity against cancer tissue by inducing apoptosis of both cancer cells and TAMs in the cancer stroma. This novel PDT thus stands as a new candidate for very effective, next-generation PDT. (C) 2014 AACR.