TY - JOUR AB - Previous metabolomic analyses of cancer have revealed elevated glutathione levels in tumors. An inhibitor of cystine uptake was identified to suppress glutathione biosynthesis, leading to ferroptosis, a novel iron‑dependent form of cell death that differs from apoptosis and necrosis. Glutamate‑cysteine ligase (GCL) is the rate‑limiting enzyme in the glutathione biosynthesis pathway. Buthionine sulfoximine (BSO), a GCL inhibitor, has previously demonstrated limited clinical benefits. Therefore, selecting patients who respond well to the inhibitor is a key approach for successful future drug development. Ferroptosis induction by BSO has not been fully examined in prior studies. Therefore, the present study investigated the pharmacological effects of BSO and the association between basal intracellular glutathione levels and sensitivity to BSO in cultured cell lines derived from various types of cancer, including those of the kidney [769P, 786‑O, A‑498, A704, ACHN, Caki‑1, Caki‑2, G401, G402, RCC4 VHL(‑/‑), RCC4 VHL(+/+), SK‑NEP‑1 and SW156] and ovaries (A2780 and A2780/CDDP). BSO was demonstrated to suppress glutathione levels and induce lipid peroxidation, thereby inhibiting cell viability. The viability‑reducing effects of BSO were attenuated by ferroptosis inhibition and enhanced by iron, indicating that BSO induced ferroptosis in cancer cells. The cell lines sensitive to BSO, including G402, tended to exhibit non‑significantly lower levels of glutathione compared with the BSO‑insensitive cell lines, including Caki‑2 (P=0.08). Patient sample data indicated the existence of a population of colorectal tumors with lower glutathione levels compared with those of matched normal tissues that might be suitable for the clinical testing of sensitivity to GCLC inhibitors. Collectively, these data suggest that GCL inhibition leads to ferroptosis in cancer cells, and that low glutathione tumor levels may be a patient selection marker for the use of GCL inhibitors in the treatment of tumors. AD - Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251‑8555, Japan Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251‑8555, Japan Institute for Advanced Bioscience, Keio University, Tsuruoka, Yamagata 997‑0052, Japan AU - Nishizawa,Satoru AU - Araki,Hideo AU - Ishikawa,Yoshinori AU - Kitazawa,Satoshi AU - Hata,Akito AU - Soga,Tomoyoshi AU - Hara,Takahito DA - 2018/06/01 DO - 10.3892/ol.2018.8447 EP - 8743 IS - 6 JO - Oncol Lett KW - cancer buthionine sulfoximine ferroptosis glutathione iron PY - 2018 SN - 1792-1074 1792-1082 SP - 8735 ST - Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors T2 - Oncology Letters TI - Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors UR - https://doi.org/10.3892/ol.2018.8447 VL - 15 ER -