Department of Clinical Pathology and Cytology, Karolinska University Hospital in Huddinge, Stockholm, Sweden.
Antioxid Redox Signal. 2013 Mar 10;18(8):888-98. doi: 10.1089/ars.2012.4885. Epub 2012 Oct 9.
Lysosomes are acidic organelles containing more than fifty hydrolases that provide for the degradation of intracellular and endocytosed materials by autophagy and heterophagy, respectively. They digest a variety of macromolecules, as well as all organelles, and their integrity is crucial. As a result of the degradation of iron-containing macromolecules (e.g., ferritin and mitochondrial components) or endocytosed erythrocytes (by macrophages), lysosomes can accumulate large amounts of iron. This iron occurs often as Fe(II) due to the acidic and reducing lysosomal environment. Fe(II) is known to catalyze Fenton reactions, yielding extremely reactive hydroxyl radicals that may jeopardize lysosomal membrane integrity during oxidative stress. This results in the release of hydrolases and redox-active iron into the cytosol with ensuing damage or cell death. Lysosomes play key roles not only in apoptosis and necrosis but also in neurodegeneration, aging, and atherosclerosis.
The damaging effect of intralysosomal iron can be hampered by endogenous or exogenous iron chelators that enter the lysosomal compartment by membrane permeation, endocytosis, or autophagy.
Cellular sensitivity to oxidative stress is enhanced by lysosomal redox-active iron or by lysosomal-targeted copper chelators binding copper (from degradation of copper-containing macromolecules) in redox-active complexes. Probably due to higher copper levels, lysosomes of malignant cells may be specifically sensitized by such chelators.
By increasing lysosomal redox-active iron or exposing cells to lysosomal-targeted copper chelators, it should be possible to enhance the sensitivity of cancer cells to radiation-induced oxidative stress or treatment with cytostatics that induce such stress.
溶酶体是含有超过 50 种水解酶的酸性细胞器，分别通过自噬和异噬作用提供细胞内和内吞物质的降解。它们消化各种大分子，以及所有细胞器，其完整性至关重要。由于含铁大分子（例如铁蛋白和线粒体成分）或内吞红细胞（由巨噬细胞）的降解，溶酶体可以积累大量的铁。由于溶酶体的酸性和还原环境，这种铁通常以 Fe(II)的形式存在。已知 Fe(II)能够催化芬顿反应，产生极其反应性的羟基自由基，在氧化应激期间可能危及溶酶体膜的完整性。这导致水解酶和氧化还原活性铁释放到细胞质中，随之而来的是损伤或细胞死亡。溶酶体不仅在细胞凋亡和坏死中起关键作用，而且在神经退行性变、衰老和动脉粥样硬化中也起关键作用。
通过膜渗透、内吞作用或自噬进入溶酶体腔的内源性或外源性铁螯合剂可以阻碍溶酶体内铁的破坏性作用。
溶酶体氧化还原活性铁或溶酶体靶向铜螯合剂与（来自含铁大分子的降解）在氧化还原活性复合物中结合铜会增强细胞对氧化应激的敏感性。由于铜水平较高，恶性细胞的溶酶体可能会被这些螯合剂特异性敏化。
通过增加溶酶体氧化还原活性铁或使细胞暴露于溶酶体靶向铜螯合剂，应该可以提高癌细胞对辐射诱导的氧化应激或诱导这种应激的细胞抑制剂治疗的敏感性。
