Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, Yamagata, Japan.
Oncotarget. 2022 Jan 26;13:224-236. doi: 10.18632/oncotarget.28185. eCollection 2022.
Glutathione is an antioxidant that has an important role in chemotherapeutic drug resistance in cancer. Cysteine is synthesized from cystine and is transported into the cell via the xCT antiporter. Another pathway for synthesizing cysteine involves intracellular methionine. We determined whether targeting the xCT represents a promising strategy for the treatment of endometrial cancer and identified factors that predict efficacy of this treatment strategy. In uterine serous carcinoma (USC) cell lines, the combination of cisplatin and the xCT inhibitor, sulfasalazine, significantly inhibited cell growth compared with single-agent cisplatin or sulfasalazine. Sulfasalazine treatment significantly decreased intracellular glutathione levels and induced apoptosis when combined with cisplatin in USC cell lines. On the one hand, the effectiveness of combined cisplatin and sulfasalazine was not evident in endometrioid carcinoma. USC cell lines exhibited increased expression of xCT and decreased expression of cystathionine gamma lyase (CGL), which is an enzyme involved in the synthesis of cysteine from methionine. On the other hand, endometrioid carcinoma cell lines exhibited increased CGL expression or decreased xCT expression. These findings suggest that using a glutathione synthesis pathway-based approach for selecting subjects for sulfasalazine treatment may be an effective strategy for circumventing glutathione-related chemotherapeutic drug resistance in endometrial carcinoma.
谷胱甘肽是一种抗氧化剂，在癌症的化疗药物耐药性中具有重要作用。半胱氨酸由胱氨酸合成，并通过 xCT 反向转运体进入细胞。合成半胱氨酸的另一种途径涉及细胞内的蛋氨酸。我们确定了靶向 xCT 是否代表治疗子宫内膜癌的一种有前途的策略，并确定了预测这种治疗策略疗效的因素。在子宫浆液性癌（USC）细胞系中，与顺铂单药或柳氮磺胺吡啶相比，顺铂和 xCT 抑制剂柳氮磺胺吡啶的联合用药显著抑制了细胞生长。柳氮磺胺吡啶与顺铂联合治疗可显著降低 USC 细胞系中的细胞内谷胱甘肽水平并诱导细胞凋亡。一方面，顺铂和柳氮磺胺吡啶联合治疗在子宫内膜样癌中并不明显。USC 细胞系表现出 xCT 表达增加和胱硫醚γ裂解酶（CGL）表达降低，CGL 是一种参与从蛋氨酸合成半胱氨酸的酶。另一方面，子宫内膜样癌细胞系表现出 CGL 表达增加或 xCT 表达降低。这些发现表明，基于谷胱甘肽合成途径的方法选择接受柳氮磺胺吡啶治疗的受试者可能是克服子宫内膜癌中与谷胱甘肽相关的化疗药物耐药性的有效策略。
