Comparative Metabolomic Profiling of Hepatocellular Carcinoma Cells Treated with Sorafenib Monotherapy vs. Sorafenib-Everolimus Combination Therapy.
Comparative Metabolomic Profiling of Hepatocellular Carcinoma Cells Treated with Sorafenib Monotherapy vs. Sorafenib-Everolimus Combination Therapy.
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索拉非尼单药治疗与索拉非尼-依维莫司联合治疗的肝细胞癌细胞代谢组学分析比较
DOI：
10.12659/msm.894669
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
Zhang JX
中科院分区：
文献类型：
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作者：
Zheng JF;Lu J;Wang XZ;Guo WH;Zhang JX
索拉非尼-依维莫司联合治疗肝细胞癌可能比索拉非尼单药治疗更有效。为了更好地理解这种作用，我们比较分析了索拉非尼、依维莫司和索拉非尼-依维莫司联合治疗HepG2细胞的代谢物组成。材料/方法采用二维HRMAS 1H-NMR代谢组学方法鉴定索拉非尼（5 μM）、依维莫司（5 μM）和联合治疗（5 μM索拉非尼+5 μM依维莫司）3个实验组的关键差异代谢物。使用MetaboAnalyst 3.0进行pathway分析。结果所有OPLS-DA模型均具有良好的实验组间分离性、高质量的拟合优度（R2）和高质量的预测优度（Q2）。索拉非尼和依维莫司在氨基酸、甲烷、丙酮酸、嘧啶、氨基酰基trna生物合成和甘油磷脂代谢方面具有不同的作用。在索拉非尼中加入依维莫司对丙酮酸、氨基酸、甲烷、乙醛酸盐和二羧酸盐、糖酵解或糖异生、甘油磷脂和嘌呤代谢产生不同的影响。结论索拉非尼与依维莫司对HepG2细胞的影响存在差异。索拉非尼优先影响甘油磷脂和嘌呤代谢，而依维莫司的加入优先影响丙酮酸、氨基酸和葡萄糖代谢。这一现象可以部分解释体内观察到的索拉非尼-依维莫司联合治疗的协同作用。
Background Sorafenib-everolimus combination therapy may be more effective than sorafenib monotherapy for hepatocellular carcinoma (HCC). To better understand this effect, we comparatively profiled the metabolite composition of HepG2 cells treated with sorafenib, everolimus, and sorafenib-everolimus combination therapy. Material/Methods A 2D HRMAS 1H-NMR metabolomic approach was applied to identify the key differential metabolites in 3 experimental groups: sorafenib (5 μM), everolimus (5 μM), and combination therapy (5 μM sorafenib +5 μM everolimus). MetaboAnalyst 3.0 was used to perform pathway analysis. Results All OPLS-DA models displayed good separation between experimental groups, high-quality goodness of fit (R2), and high-quality goodness of predication (Q2). Sorafenib and everolimus have differential effects with respect to amino acid, methane, pyruvate, pyrimidine, aminoacyl-tRNA biosynthesis, and glycerophospholipid metabolism. The addition of everolimus to sorafenib resulted in differential effects with respect to pyruvate, amino acid, methane, glyoxylate and dicarboxylate, glycolysis or gluconeogenesis, glycerophospholipid, and purine metabolism. Conclusions Sorafenib and everolimus have differential effects on HepG2 cells. Sorafenib preferentially affects glycerophospholipid and purine metabolism, while the addition of everolimus preferentially affects pyruvate, amino acid, and glucose metabolism. This phenomenon may explain (in part) the synergistic effects of sorafenib-everolimus combination therapy observed in vivo.