Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepcion, Chile; Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Concepción, Chile.
Department of Instrumental Analysis, Faculty of Pharmacy, University of Concepcion, Chile.
Life Sci. 2023 Nov 15;333:122166. doi: 10.1016/j.lfs.2023.122166. Epub 2023 Oct 10.
Ovarian cancer presents a significant challenge due to its high rate of chemoresistance, which complicates the effectiveness of drug-response therapy. This study provides a comprehensive metabolomic analysis of ovarian cancer cell lines OVCAR-3 and SK-OV-3, characterizing their distinct metabolic landscapes. Metabolomics coupled with chemometric analysis enabled us to discriminate between the metabolic profiles of these two cell lines. The OVCAR-3 cells, which are sensitive to doxorubicin (DOX), exhibited a preference for biosynthetic pathways associated with cell proliferation. Conversely, DOX-resistant SK-OV-3 cells favored fatty acid oxidation for energy maintenance. Notably, a marked difference in glutathione (GSH) metabolism was observed between these cell lines. Our investigations further revealed that GSH depletion led to a profound change in drug sensitivity, inducing a shift from a cytostatic to a cytotoxic response. The results derived from this comprehensive metabolomic analysis offer potential targets for novel therapeutic strategies to overcome drug resistance. Our study suggests that targeting the GSH pathway could potentially enhance chemotherapy's efficacy in treating ovarian cancer.
卵巢癌由于其高化疗耐药率，给治疗带来了巨大的挑战，这使得药物反应治疗的效果变得复杂。本研究对卵巢癌细胞系 OVCAR-3 和 SK-OV-3 进行了全面的代谢组学分析，描绘了它们独特的代谢特征。代谢组学与化学计量学分析相结合，使我们能够区分这两种细胞系的代谢特征。对多柔比星（DOX）敏感的 OVCAR-3 细胞表现出对与细胞增殖相关的生物合成途径的偏好。相反，对 DOX 耐药的 SK-OV-3 细胞则倾向于利用脂肪酸氧化来维持能量。值得注意的是，这两种细胞系之间的谷胱甘肽（GSH）代谢存在明显差异。我们的研究进一步表明，GSH 的耗竭会导致药物敏感性发生深刻变化，从细胞抑制作用转变为细胞毒性作用。这项全面代谢组学分析的结果为克服药物耐药性提供了新的治疗策略的潜在靶点。我们的研究表明，靶向 GSH 途径可能会增强化疗治疗卵巢癌的效果。
