The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2018, Vol.391 (1), p.71-82
• Main Authors: Liow, K. Y., Chow, Sek C.
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Alanine; Apoptosis; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Buthionine sulfoximine; Cathepsin B; Cathepsin B - antagonists & inhibitors; Cathepsin B - metabolism; Cell death; Cell Death - drug effects; Cell Death - physiology; Cysteine Proteinase Inhibitors - toxicity; Depletion; Dose-Response Relationship, Drug; Glutathione; Humans; Intracellular; Jurkat Cells; Ketones; Leukemia; Leukemia, T-Cell - metabolism; Low concentrations; Lymphocytes; Lymphocytes T; Neurosciences; Original Article; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pharmacology/Toxicology; Phenylalanine; Reactive Oxygen Species; Toxicity
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-017-1436-6

The cathepsin B inhibitor benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was recently found to induce apoptosis at low concentrations in Jurkat T cells, while at higher concentrations, the cells die of necrosis. In the present study, we showed that z-FA-CMK readily depletes intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) generation. The toxicity of z-FA-CMK in Jurkat T cells was completely abrogated by N -acetylcysteine (NAC), suggesting that the toxicity mediated by z-FA-CMK is due to oxidative stress. We found that l -buthionine sulfoximine (BSO) which depletes intracellular GSH through the inhibition of GSH biosynthesis in Jurkat T cells did not promote ROS increase or induce cell death. However, NAC was still able to block z-FA-CMK toxicity in Jurkat T cells in the presence of BSO, indicating that the protective effect of NAC does not involve GSH biosynthesis. This is further corroborated by the protective effect of the non-metabolically active d -cysteine on z-FA-CMK toxicity. Furthermore, in BSO-treated cells, z-FA-CMK-induced ROS increased which remains unchanged, suggesting that the depletion of GSH and increase in ROS generation mediated by z-FA-CMK may be two separate events. Collectively, our results demonstrated that z-FA-CMK toxicity is mediated by oxidative stress through the increase in ROS generation.