Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany.
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany.
Photodiagnosis Photodyn Ther. 2021 Dec;36:102478. doi: 10.1016/j.pdpdt.2021.102478. Epub 2021 Aug 8.
Due to an increased elimination of reactive oxygen species (ROS), in particular hydrogen peroxide (HO), overexpression of glutathione peroxidase 1 (GP1) can lead to an attenuation of apoptosis and development of resistance in cancer cells, thereby promoting tumor cell survival. Consequently, GP1 inhibitors have the potential to be used in cancer therapy as they support oxidative stress in cancer cells. Similarly, photodynamic therapy (PDT) induces oxidative stress in cancer cells by the formation of ROS upon illumination. Thus, both methods of treatment might act in synergy when used in combination.
To investigate this hypothesis, combinations of the known GP1 inhibitors 9-chloro-6-ethyl-6H-[1,2,3,4,5]pentathiepino[6,7-b]indole (CEPI) or mercaptosuccinic acid (MSA) with PDT induced by the photosensitizer (PS) temoporfin (5,10,15,20-tetra(m-hydroxyphenyl)chlorin, mTHPC) were studied in vitro. This new combinatory approach was intended to accumulate ROS formed during PDT via blockage of GP1-catalyzed HO degradation, and thus to enhance PDT-induced phototoxicity. Five human cancer cell lines from tumor origins treatable with PDT were utilized to investigate ROS generation, apoptosis induction, and cell cycle distribution.
Synergy was identified with both GP1 inhibitors, but not in all cell lines. ROS levels were increased after combined treatment with mTHPC and CEPI, but not MSA, in some cell lines, indicating that oxidative stress and ROS accumulation were enhanced by CEPI. Surprisingly, enhanced apoptosis induction was also observed with MSA afterwards, suggesting that other pathways contributed to the initiation of apoptosis. Cell cycle analysis confirmed apoptosis induction via the detection of DNA fragmentation.
A combination of GP1 inhibitors with mTHPC-PDT has the potential to generate synergistic effects and to increase overall phototoxicity, but the success of this combination approach was dependent on cancer type, and even antagonistic effects can occur.
由于活性氧（ROS），特别是过氧化氢（HO）的消除增加，谷胱甘肽过氧化物酶 1（GP1）的过表达可导致癌细胞凋亡减弱和耐药性发展，从而促进肿瘤细胞存活。因此，GP1 抑制剂有可能用于癌症治疗，因为它们支持癌细胞中的氧化应激。同样，光动力疗法（PDT）通过光照下形成 ROS 诱导癌细胞中的氧化应激。因此，当联合使用时，这两种治疗方法可能会协同作用。
为了验证这一假设，研究了已知的 GP1 抑制剂 9-氯-6-乙基-6H-[1,2,3,4,5]戊噻吩并[6,7-b]吲哚（CEPI）或巯基琥珀酸（MSA）与光敏剂（PS）替莫泊芬（5,10,15,20-四（m-羟基苯基）氯，mTHPC）诱导的 PDT 的组合。这种新的组合方法旨在通过阻断 GP1 催化的 HO 降解来积累 PDT 过程中形成的 ROS，从而增强 PDT 诱导的光毒性。利用来自可通过 PDT 治疗的肿瘤起源的五种人类癌细胞系来研究 ROS 生成、细胞凋亡诱导和细胞周期分布。
在所有细胞系中均未发现两种 GP1 抑制剂的协同作用，但在一些细胞系中发现了协同作用。在一些细胞系中，在用 mTHPC 和 CEPI 联合处理后，ROS 水平增加，但在用 MSA 处理后并未增加，这表明 CEPI 增强了氧化应激和 ROS 积累。令人惊讶的是，随后也观察到 MSA 诱导的增强凋亡，这表明其他途径有助于启动凋亡。细胞周期分析通过检测 DNA 片段化证实了通过凋亡诱导。
GP1 抑制剂与 mTHPC-PDT 的联合具有产生协同作用和增加总体光毒性的潜力，但这种联合方法的成功取决于癌症类型，甚至可能产生拮抗作用。
