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

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Abstract

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.

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This work was supported by the internal funding provided by Monash University Malaysia.

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  1. School of Science, Monash University Malaysia, Jalan Lagoon Selatan, 46150, Bandar Sunway, Selangor Darul Ehsan, Malaysia

    K. Y. Liow & Sek C. Chow

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Liow, K.Y., Chow, S.C. The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress. Naunyn-Schmiedeberg's Arch Pharmacol 391, 71–82 (2018). https://doi.org/10.1007/s00210-017-1436-6

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