Study on the Synergistic Mechanism of Photodynamic Therapy Combined With Ferroptosis Inducer to Induce Ferroptosis in Cholangiocarcinoma

IF 2.2 3区医学 Q2 DERMATOLOGY

Lasers in Surgery and Medicine Pub Date : 2024-10-29 DOI:10.1002/lsm.23857

Sifan Dong, Shiqi An, Qifan Liu, Xujia Wang, Yongmei Hu, An Jiang

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引用次数: 0

Abstract

Background

Photodynamic therapy (PDT) induced lipid peroxidation reaction can lead to necrosis and apoptosis of extrahepatic cholangiocarcinoma (ECC) cells, reducing the tumor load. However, the depth of action of PDT is shallow, and its therapy efficacy is weak, making it difficult to achieve eradication even with multiple treatments.

Objectives

This study aims to investigate the mechanism and main pathways of ferroptosis in cholangiocarcinoma under Hematoporphyrin-mediated photodynamic therapy, and to compare the effects of different ferroptosis inducers on photodynamic therapy-induced ferroptosis in cholangiocarcinoma. To provide an experimental basis for selecting appropriate ferroptosis-inducing agents and synergizing with photodynamic therapy during the clinical perioperative period.

Methods

The Cell Counting Kit-8 (CCK-8) was used to examine the cytotoxicity of cholangiocarcinoma cells following PDT. Flow cytometry was used to detect apoptotic cell percentage and cell cycle changes to assess the enhanced photodynamic production of reactive oxygen species (ROS) by different ferroptosis inducers, confocal imaging was used to de-assay ROS content. Western blot analysis was employed to detect the expression of GPX4 、FSP1、ASCL4 and SLC7A11. Furthermore, a fluorescence spectrophotometric assay was used to quantify the alterations in lipid peroxides (MDA, LPO, GSH, and Fe²⁺).

Results

The combination of PDT with Lenvatinib or Erastin resulted in increased ROS levels, and decreased GSH content, tumor cells were inhibited in the G2 phase, and the proportion of apoptotic cells increased. Additionally, GPX4, FSP1, and SLC7A11 protein expression decreased, whereas ASCL4 increased This was accompanied by heightened levels of Fe²⁺, LPO, and MDA. Induction of the ferroptosis pathway was observed to enhance the therapeutic efficacy of PDT.

Conclusion

Our findings suggest that Erastin or Lenvatinib can enhance the induction of ferroptosis in cholangiocarcinoma cells by photodynamic therapy by increasing intracellular ROS and inhibiting intracellular antioxidant pathways.

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光动力疗法与铁突变诱导剂联合诱导胆管癌铁突变的协同机制研究

背景：光动力疗法（PDT）诱导的脂质过氧化反应可导致肝外胆管癌（ECC）细胞坏死和凋亡，减轻肿瘤负荷。但PDT作用深度较浅，疗效较弱，即使多次治疗也难以达到根治的目的：本研究旨在探讨血卟啉介导的光动力疗法下胆管癌铁细胞凋亡的机制和主要途径，比较不同铁细胞凋亡诱导剂对光动力疗法诱导胆管癌铁细胞凋亡的影响。为临床围手术期选择合适的铁蛋白沉着诱导剂并与光动力疗法协同提供实验依据：方法：使用细胞计数试剂盒-8（CCK-8）检测光动力疗法后胆管癌细胞的细胞毒性。流式细胞术用于检测凋亡细胞的百分比和细胞周期的变化，以评估不同的铁凋亡诱导剂在光动力作用下产生的活性氧（ROS）的增强情况。采用 Western 印迹分析检测 GPX4 、FSP1、ASCL4 和 SLC7A11 的表达。此外，还采用荧光分光光度法量化脂质过氧化物（MDA、LPO、GSH和Fe2+）的变化：结果：PDT与仑伐替尼或Erastin联用后，ROS水平升高，GSH含量降低，肿瘤细胞在G2期受到抑制，凋亡细胞比例增加。此外，GPX4、FSP1 和 SLC7A11 蛋白表达减少，而 ASCL4 蛋白表达增加。据观察，铁变态反应途径的诱导增强了光动力疗法的疗效：我们的研究结果表明，Erastin 或 Lenvatinib 可通过增加细胞内 ROS 和抑制细胞内抗氧化通路，增强光动力疗法对胆管癌细胞铁氧化的诱导作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Lasers in Surgery and Medicine 医学-外科

CiteScore

5.40

自引率

12.50%

发文量

119

审稿时长

1 months

期刊介绍： Lasers in Surgery and Medicine publishes the highest quality research and clinical manuscripts in areas relating to the use of lasers in medicine and biology. The journal publishes basic and clinical studies on the therapeutic and diagnostic use of lasers in all the surgical and medical specialties. Contributions regarding clinical trials, new therapeutic techniques or instrumentation, laser biophysics and bioengineering, photobiology and photochemistry, outcomes research, cost-effectiveness, and other aspects of biomedicine are welcome. Using a process of rigorous yet rapid review of submitted manuscripts, findings of high scientific and medical interest are published with a minimum delay.