Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.105
Extracellular Concentration of L-Cystine Determines the Sensitivity to System xc - Inhibitors
Md Abdullah and Seung Jin Lee*
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
*E-mail: s.j.lee@cnu.ac.kr
Tel: +82-42-821-5940, Fax: +82-42-822-5343
Received: June 25, 2021; Revised: September 10, 2021; Accepted: September 16, 2021; Published online: October 19, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Targeting the cystine/glutamate exchange transporter, system xc -, is a promising anticancer strategy that induces ferroptosis, which is a distinct form of cell death mediated by iron-dependent lipid peroxidation. The concentration of L-cystine in culture medium is higher than the physiological level. This study was aimed to evaluate the effects of L-cystine concentration on the efficacy of ferroptosis inducers in hepatocellular carcinoma cells. This study showed that treatment with sulfasalazine or erastin, a system xc - inhibitor, decreased the viability of Huh6 and Huh7 cells in a dose-dependent manner, and the degree of growth inhibition was greater in medium containing a physiological L-cystine concentration of 83 μM than in commercial medium with a concentration of 200 μM L-cystine. However, RSL3, a glutathione peroxidase 4 inhibitor, decreased cell viability to a similar extent in media containing both L-cystine concentrations. Sulfasalazine and erastin significantly increased the percentages of propidium iodide-positive cells in media with 83 μM L-cystine, but not in media with 200 μM L-cystine. Sulfasalazine- or erastin-induced accumulation of lipid peroxidation as monitored by C11-BODIPY probe was higher in media with 83 μM L-cystine than in media with 200 μM L-cystine. In contrast, the changes in the percentages of propidium iodide-positive cells and lipid peroxidation by RSL3 were similar in both media. These results showed that sulfasalazine and erastin, but not RSL3, were efficacious under conditions of physiological Lcystine concentration, suggesting that medium conditions would be crucial for the design of a bioassay for system xc - inhibitors.
Keywords: L-Cystine, Sulfasalazine, Erastin, Ferroptosis, System xc -, Glutathione peroxidase 4


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