Pharmacologic manipulations of mitochondrial membrane potential (ΔΨm) selectively in glioma cells
Pharmacologic manipulations of mitochondrial membrane potential (ΔΨm) selectively in glioma cells
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DOI：
10.1007/s11060-006-9201-6
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发表时间：
2007-01-01
影响因子：
3.9
通讯作者：
Marcorelles, Pascale
中科院分区：
文献类型：
--
作者：
Griguer, Corinne E.;Oliva, Claudia R.;Marcorelles, Pascale
代谢控制理论将生物能量学原理应用于复杂疾病的控制或管理。由于新陈代谢是所有生物表型的一般过程，新陈代谢的变化可能会改变表型。因此，我们有理由认为，对细胞能量可用性的实验调节可能会改变细胞表型和细胞功能，这些细胞功能对肿瘤的发展至关重要，包括细胞分裂。这项研究的目的是确定OMX-2是否能够靶向癌细胞中的线粒体并引发细胞死亡。OMX-2是一种甲基醌系统，旨在从线粒体复合体中传递电子。应用流式细胞术、细胞活力分析和三磷酸腺苷测定，我们发现OMX-2在不引发细胞死亡的情况下显著降低了Delta Psim。相反，已知的电子传输链(ETC)阻断剂降低了Delta Psim并引发了细胞死亡。当用OMX-2处理正常细胞时，既不会触发Delta Psi，也不会触发细胞死亡。此外，OMX-2还可调节细胞内ATP，减少胶质瘤细胞的数量。细胞周期分析显示，OMX-2诱导细胞周期可逆性停滞于G1/S期，2-脱氧葡萄糖(2-DOG)对糖酵解的抑制作用与OMX-2协同作用，触发细胞死亡。总体而言，这些结果表明，有可能通过降低Delta Psim来选择性地靶向癌细胞，并诱导细胞周期停止，而不会引发细胞死亡。此外，旨在同时作用于糖酵解和氧化磷酸化的药物方法可以被认为是一种选择性杀死癌细胞的新方法。
Metabolic control theory applies principles of bioenergetics for the control or management of complex diseases. Since metabolism is a general process underlying all biologic phenotypes, changes in metabolism can potentially modify phenotype. Therefore, it is reasonable to assume that experimental modulation of the availability of cellular energy can potentially alter cell phenotypes and cell functions critical to tumor progression including cell division. The purpose of this study was to determine if OMX-2, a methylquinone system designed to shuttle electrons from mitochondrial complexes, was able to target mitochondria in cancer cells and trigger cell death. Using flow cytometry, cell viability assays, and ATP measurements, we found that OMX-2 differentially decreased Delta Psi m without triggering cell death. In contrast, known blockers of the Electron Transport Chain (ETC) decreased Delta Psi m and triggered cell death. When normal cells were treated with OMX-2, neither Delta Psi m or cell death was triggered. Furthermore, OMX-2 modulated intracellular ATP and decreased cell numbers of glioma cells. Cell cycle analysis indicated that OMX-2 induced a reversible cell cycle arrest in G1/S. Finally, impairment of glycolysis by 2-Deoxyglucose (2-DOG) acted synergistically with OMX-2 to trigger cell death. Overall, these results indicate that it is possible to selectively target cancer cells by decreasing Delta Psi m and induced cell cycle arrest without triggering cell death. Moreover, pharmacological approaches designed to act on both glycolysis and oxidative phosphorylation can be considered as a new approach to selectively kill cancer cells.