文章：

靶向癌症的氧化还原催化：锰卟啉与抗坏血酸协同诱导选择性氧化应激与坏死性细胞死亡

Targeting Cancer with Redox Catalysis: Manganese Porphyrins and Ascorbate Synergistically Induce Selective Oxidative Stress and Necrotic Cell Death

原文发布日期：22 November 2025

DOI: 10.3390/cancers17233736

类型: Article

开放获取: 是

英文摘要：

Background: The combination of manganese porphyrins (MnPs) and ascorbate (ASC) represents a promising redox-based therapeutic approach for selectively targeting cancer cells. We investigated the cytotoxic effects of two structurally distinct MnPs (MnTPPS and MnF2BMet) with differing lipophilicity and potential membrane permeability in combination with ASC. Methods: Cancer cell lines (MCF-7, PANC-1, U87, T98G, AT-2) and normal human dermal fibroblasts (HDFs) were treated with MnTPPS and MnF2BMet in the absence or presence of ASC. Viability, migration potential, and intracellular oxidative stress were assessed using single-cell methods. Results: MnPs alone exhibited no intrinsic cytostatic or cytotoxic activity, as confirmed by proliferation, viability, and motility assays. When combined with ASC, both MnTPPS and MnF2BMet significantly enhanced ASC-induced oxidative stress, leading to lipid peroxidation, glutathione depletion, mitochondrial dysfunction, and cell membrane disruption. Time-lapse microscopy revealed rapid necrotic cell death under co-treatment. Catalase fully abolished cytotoxicity, indicating the essential role of hydrogen peroxide. In contrast, dehydroascorbate (DHA), which increases intracellular ASC levels, did not induce the same toxicity, suggesting that extracellular ROS generation contributes predominantly to the observed effects. Normal fibroblasts were minimally affected, supporting the MnPs–ASC system’s selectivity toward cancer cells. Conclusions: MnTPPS and MnF2BMet enhance extracellular oxidation of ascorbate and subsequent ROS production, leading to selective oxidative-stress-mediated cancer cell death. This study supports the potential of MnPs–ASC redox catalysis as a complementary oxidative-stress-based anticancer strategy and highlights the need for further mechanistic and structure–activity investigations.

摘要翻译： 

背景：锰卟啉（MnPs）与抗坏血酸（ASC）的组合是一种基于氧化还原反应、选择性靶向癌细胞的有前景的治疗策略。本研究探讨了两种结构不同、具有不同亲脂性和潜在膜通透性的锰卟啉（MnTPPS与MnF2BMet）与ASC联用时的细胞毒性效应。方法：在有无ASC存在的情况下，用MnTPPS和MnF2BMet处理癌细胞系（MCF-7、PANC-1、U87、T98G、AT-2）及正常人真皮成纤维细胞（HDFs）。采用单细胞方法评估细胞活力、迁移潜能及细胞内氧化应激水平。结果：增殖、活力和运动能力检测证实，单独使用MnPs未表现出固有的细胞抑制或细胞毒性活性。当与ASC联用时，MnTPPS和MnF2BMet均显著增强了ASC诱导的氧化应激，导致脂质过氧化、谷胱甘肽耗竭、线粒体功能障碍和细胞膜破坏。延时显微成像显示联合处理可迅速引发细胞坏死性死亡。过氧化氢酶能完全消除细胞毒性，表明过氧化氢在此过程中起关键作用。相比之下，能提高细胞内ASC水平的脱氢抗坏血酸（DHA）并未引发相同毒性，提示细胞外活性氧的生成是观察到的效应主要来源。正常成纤维细胞受影响极小，这支持了MnPs–ASC体系对癌细胞的选择性。结论：MnTPPS和MnF2BMet能增强抗坏血酸的细胞外氧化及后续活性氧生成，从而导致选择性氧化应激介导的癌细胞死亡。本研究证实了MnPs–ASC氧化还原催化作为一种补充性氧化应激抗癌策略的潜力，并强调需进一步开展机制及构效关系研究。

原文链接：

Targeting Cancer with Redox Catalysis: Manganese Porphyrins and Ascorbate Synergistically Induce Selective Oxidative Stress and Necrotic Cell Death