L-Buthionine-(S,R)-sulfoximine (L-Butionine sulfoximine) is a glutathione synthesis inhibitor [1]. L-Buthionine-(S,R)-sulfoximine specifically inhibits the activity of γ-glutamylcysteine synthetase, thereby significantly reducing intracellular glutathione (GSH) levels [2-3]. L-Buthionine-(S,R)-sulfoximine is often used in cancer research [4].
In fibroblasts, treatment with L-Buthionine-(S,R)-sulfoximine (200-500μM; 48h) showed dose-dependent enhancement of cell death within 48 hours [5]. In SCLC cells, the GSH content in the cells decreased by 57% after treatment with L-Buthionine-(S,R)-sulfoximine (500μM; 30h) [6]. In retinal ganglion cells (RGCs), L-Buthionine-(S,R)-sulfoximine (0.75mM; 24h, 48h) administration resulted in oxidative stress caused by glutathione depletion, and RGC survival rate was significantly decreased [7].
In B6C3F1 mice, after treatment with L-Buthionine-(S,R)-sulfoximine (0, 252mg/kg, 536.995mg/kg, 1502mg/kg; po; 14d), the GSH levels in mice were significantly reduced in a dose-dependent manner [8]. In HT1080 cells subcutaneous tumor mouse model, treatment with L-Buthionine-(S,R)-sulfoximine (600mg/kg; iv; 48h) produced a 60% reduction of GSH plasma levels and greater than 95% reduction in GSH tumor levels in both parental and multidrug-resistant tumors [9].
References:
[1]. Fruehauf J P, Zonis S, AL‐BASSAM M, et al. Selective and Synergistic Activity of L‐S, R‐Buthionine Sulfoximine on Malignant Melanoma Is Accompanied by Decreased Expression of Glutathione‐S‐Transferase[J]. Pigment cell research, 1997, 10(4): 236-249.
[2]. Reliene R, Schiestl R H. Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice[J]. Carcinogenesis, 2006, 27(2): 240-244.
[3]. Nishizawa S, Araki H, Ishikawa Y, et al. Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors[J]. Oncology Letters, 2018, 15(6): 8735-8743.
[4]. Seo Y J, Lee J W, Lee E H, et al. Role of glutathione in the adaptive tolerance to H2O2[J]. Free radical biology and medicine, 2004, 37(8): 1272-1281.
[5]. Miyauchi A, Kouga T, Jimbo E F, et al. Apomorphine rescues reactive oxygen species-induced apoptosis of fibroblasts with mitochondrial disease[J]. Mitochondrion, 2019, 49: 111-120.
[6]. Lee C S. Effect of Depletion and Oxidation of Cellular GSH on Cytotoxicity of Mitomycin Small Cell Lung Cancer Cells[J]. Biomolecules & Therapeutics, 2004, 12(2): 92-100.
[7]. del Valle Bessone C, Fajreldines H D, de Barboza G E D, et al. Protective role of melatonin on retinal ganglionar cell: In vitro an in vivo evidences[J]. Life Sciences, 2019, 218: 233-240.
[8]. Watanabe T, Sagisaka H, Arakawa S, et al. A novel model of continuous depletion of glutathione in mice treated with L-buthionine (S, R)-sulfoximine[J]. The Journal of toxicological sciences, 2003, 28(5): 455-469.
[9]. Vanhoefer U, Cao S, Minderman H, et al. d, l-buthionine-(S, R)-sulfoximine potentiates in vivo the therapeutic efficacy of doxorubicin against multidrug resistance protein-expressing tumors[J]. Clinical cancer research: an official journal of the American Association for Cancer Research, 1996, 2(12): 1961-1968.
L-Buthionine-(S,R)-sulfoximine (L-Butionine sulfoximine)是一种谷胱甘肽合成抑制剂 [1]。L-Buthionine-(S,R)-sulfoximine特异性抑制γ-谷氨酰半胱氨酸合成酶的活性，从而显著降低细胞内谷胱甘肽（GSH）水平 [2-3]。L-Buthionine-(S,R)-sulfoximine常用于癌症研究 [4]。
在成纤维细胞中，用L-Buthionine-(S,R)-sulfoximine（200-500μM；48h）处理后，48小时内细胞死亡呈剂量依赖性增加 [5]。在小细胞肺癌（SCLC）细胞中，用L-Buthionine-(S,R)-sulfoximine（500μM；30h）处理后，细胞内GSH含量下降了57% [6]。在视网膜神经节细胞（RGC）中，用L-Buthionine-(S,R)-sulfoximine（0.75mM；24h，48h）处理后，由于谷胱甘肽耗竭导致氧化应激，RGC存活率显著降低 [7]。
在B6C3F1小鼠中，用L-Buthionine-(S,R)-sulfoximine（0，252mg/kg、536.995mg/kg，1502mg/kg；po；14d）治疗后，小鼠体内的GSH水平显著降低，且呈剂量依赖性 [8]。在HT1080细胞皮下肿瘤小鼠模型中，用L-Buthionine-(S,R)-sulfoximine（600mg/kg；iv；48h）治疗后，小鼠血浆GSH水平降低了60%，亲本肿瘤和耐多药肿瘤中的GSH肿瘤水平降低了95%以上 [9]。