Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG.
Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG.
复制标题
靶向癌细胞的能量代谢：NCL-240 和 2-DG 联合给药。
DOI：
10.1016/j.ijpharm.2017.08.095
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发表时间：
2017
影响因子：
5.8
通讯作者：
Torchilin,Vladimir
中科院分区：
文献类型：
--
作者：
Pattni,BhushanS;Jhaveri,Aditi;Dutta,Ivy;Baleja,JamesD;Degterev,Alexei;Torchilin,Vladimir
癌细胞增加新陈代谢，以产生生长和增殖所需的能量和生物分子。因此，能量代谢途径可能成为抗癌治疗的靶点。NCL-240是第二代抗癌药物，属于PITenins类PI3K-Akt抑制剂。我们的分析表明，NCL-240导致线粒体氧化磷酸化和糖酵解的中断，TCA循环产生的氨基酸产物的核磁共振峰丢失，仅存在乳酸峰和葡萄糖峰的丢失就是明证。在多个细胞系的早期概念验证研究中，NCL-240与2-脱氧-d-葡萄糖(2-DG)联合使用。2-DG可增强NCL-240诱导的细胞死亡反应，其细胞毒性结果与低血糖条件下相似。在进一步的研究中，将包裹在磷脂酰胆碱/胆固醇脂质体中的NCL-240与自由溶解的2-DG结合。对经NCL-240/2-DG组合处理的A2780敏感株和耐药株的细胞周期分析表明，80-90%的细胞处于G0/G1期停滞，表明无法生长和分裂。体外癌细胞单层模型中的细胞毒性研究证实了细胞周期分析的结果。在多个细胞系中，联合治疗的细胞毒性比对照组和单独治疗的细胞毒性显著改善。NCI/ADR-RES癌细胞球体进一步证明了NCL-240/2-DG组合的有效性。
Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive and resistant strains of A2780 cells treated with combinations of NCL-240/2-DG pointed to a G0/G1 phase arrest for 80–90% of the total, indicating an inability to grow and divide. Cytotoxicity studies within vitrocancer cell monolayer models confirmed the results of cell cycle analysis. Significant improvements in cytotoxicity with combination treatments over control and individual treatments were seen in multiple cell lines. NCI/ADR-RES cancer cell spheroids further demonstrated the effectiveness of a NCL-240/2-DG combination.