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首页> 外文会议>Optical methods for tumor treatment and detection: mechanisms and techniques in photodynamic therapy XX >Signaling From Lysosomes to Mitochondria Sensitizes Cancer Cells to Photodynamic Treatment
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Signaling From Lysosomes to Mitochondria Sensitizes Cancer Cells to Photodynamic Treatment

机译：从溶酶体到线粒体的信号刺激癌细胞进行光动力治疗。

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Previously, we showed that photosensitizers that localize to lysosomes are more effective in killing cancer cells than ones directed to mitochondria after photodynamic treatment (PDT). The photosensitizer, phthalocyanine 4 (Pc 4), localizes primarily to mitochondrial membranes in cancer cells, resulting in mitochondria-mediated cell death. However, analogues of Pc 4 (e.g., Pc 181) that primarily target lysosomes still produce mitochondria-mediated cell death, although the time course is slower compared to Pc 4-PDT. In A431 epidermoid carcinoma cells, these new analogues preferentially localized in lysosomes were highly efficient in inducing apoptotic cell death. To assess further how lysosomes contribute to PDT, we monitored cell killing of A431 cells after Pc 4-PDT in the presence and absence of bafilomycin, an inhibitor of the acidic vacuolar proton pump that collapses the pH gradient of the lysosomal/endosomal compartment. Bafilomycin by itself was not toxic but greatly enhanced Pc 4-PDT-induced mitochondrial depolarization and cell killing. Both depolarization and cell killing were substantially prevented by iron chelators. The fact that Pc 4-PDT plus bafilomycin treatment did not induce lysosomal membrane damage prior to mitochondrial depolarization suggests that bafilomycin instead induced release of redox active iron from lysosomes into the cytosol that further translocated into mitochondria, where iron-mediated free radical formation occurred. In conclusion, agents that disturb lysosomal function could potentially be used as adjuvants with mitochondrion-targeted photosensitizers to enhance phototoxicity.
机译：以前，我们证明了定位于溶酶体的光敏剂在杀死癌细胞方面比光动力治疗（PDT）后针对线粒体的光敏剂更有效。光敏剂酞菁4（Pc 4）主要定位于癌细胞中的线粒体膜，导致线粒体介导的细胞死亡。然而，尽管时间过程比Pc 4-PDT慢，但主要靶向溶酶体的Pc 4类似物（例如Pc 181）仍会产生线粒体介导的细胞死亡。在A431表皮样癌细胞中，这些新的类似物优先位于溶酶体中，在诱导凋亡性细胞死亡中非常有效。为了进一步评估溶酶体如何促进PDT，我们在存在和不存在巴氟霉素的情况下监测了Pc 4-PDT后A431细胞的杀伤作用，巴氟霉素是酸性液泡质子泵的抑制剂，可破坏溶酶体/内膜区室的pH梯度。 Bafilomycin本身无毒，但大大增强了Pc 4-PDT诱导的线粒体去极化和细胞杀伤作用。铁螯合剂基本上防止了去极化和细胞杀伤。 Pc 4-PDT加杆状霉素处理不会在线粒体去极化之前诱导溶酶体膜损伤，这一事实表明杆状霉素反而导致氧化还原活性铁从溶酶体释放到细胞溶质中，并进一步转移到线粒体中，在此发生铁介导的自由基形成。总之，干扰溶酶体功能的药物可与线粒体靶向的光敏剂一起用作佐剂，以增强光毒性。

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