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Molecular factors in cell (and tumor) response to photodynamic therapy: The role of Bid

机译:细胞(和肿瘤)对光动力疗法反应的分子因素:出价的作用

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The phthalocyanine photosensitizer Pc 4 binds preferentially to mitochondrial and endoplasmic reticulum membranes. Upon photoirradiation of Pc 4-loaded cells, membrane components, including Bcl-2, are photodamaged and apoptosis is triggered. We recently prepared analogues of Pc 4 containing two axial ligands, one identical to the single ligand in Pc 4, and the other containing one or two hydroxyl groups on a dimethylsiloxy alkyl chain. Pc 181 is representative of this group of photosensitizers. In MCF-7 human breast cancer cells, the new analogues preferentially localized in lysosomes and were highly efficient in inducing apoptosis and overall cell death. The Bcl-2 family member Bid is required for signaling to mitochondria for apoptosis in response to primary lysosomal photodamage. To further evaluate the role of Bid, we compared the effects of PDT with Pc 4 or Pc 181 in wild-type murine embryonic fibroblasts and those knocked out for Bid. We find that the two cell lines are equally sensitive to killing by Pc 4-PDT, but the Bid"'" cells are significantly more resistant to killing and apoptosis induction by Pc 181-PDT than are the Bid~+/+ cells. The data show that low levels of lysosomal photodamage are not alone lethal and that a specific defect in a factor required for apoptosis can severely compromise cell response to PDT.
机译:酞菁光敏剂Pc 4优先与线粒体和内质网膜结合。对装载Pc 4的细胞进行光辐照后,包括Bcl-2在内的膜成分会受到光损伤,并触发凋亡。我们最近制备了包含两个轴向配体的Pc 4类似物,一个与Pc 4中的单个配体相同,另一个在二甲基甲硅烷氧基烷基链上包含一个或两个羟基。 PC 181代表了这组光敏剂。在MCF-7人乳腺癌细胞中,新的类似物优先位于溶酶体中,并且在诱导细胞凋亡和总体细胞死亡方面非常有效。 Bcl-2家族成员Bid是信号传导至线粒体以响应原发性溶酶体光损伤的凋亡。为了进一步评估Bid的作用,我们比较了PDT与Pc 4或Pc 181在野生型鼠胚胎成纤维细胞和敲除Bid中的作用。我们发现这两种细胞系对Pc 4-PDT杀伤同样敏感,但是与Bid _ + / +细胞相比,Bid“”“细胞对Pc 181-PDT的杀伤和凋亡诱导的抵抗力明显更高。数据表明,溶酶体光损伤的低水平并非单独具有致命性,并且凋亡所需因子中的特定缺陷会严重损害细胞对PDT的反应。

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