Therapeutic advantage of combining calcium channel blockers and TRAIL in prostate cancer
Therapeutic advantage of combining calcium channel blockers and TRAIL in prostate cancer
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DOI：
10.1158/1535-7163.mct-06-0011
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发表时间：
2006-08-01
影响因子：
5.7
通讯作者：
Kumar, M. Vijay
中科院分区：
文献类型：
--
作者：
Kaddour-Djebbar, Ismail;Lakshmikanthan, Vijayabaskar;Kumar, M. Vijay
细胞内钙的破坏引发多种细胞损伤过程，如细胞凋亡。在正常细胞中，线粒体中的Ca2+水平较低，而在凋亡细胞中，Ca2+增加。线粒体通过称为单转运体的内膜通道摄取Ca2+，并通过Na+/Ca2+交换器将其挤出细胞质。在cgp处理的细胞中，线粒体中Ca2+超载导致其损伤，从而影响细胞功能和存活。这些实验的目的是确定线粒体钙（[Ca2+](m)）在前列腺癌细胞凋亡中的重要性。此外，我们还研究了增加[Ca2+](m)和用肿瘤坏死因子相关凋亡诱导配体（TRAIL）治疗细胞的优势，TRAIL是一种有效的凋亡剂。我们的研究结果表明，在这些处理条件下，使用苯并噻唑平CGP-37157 （CGP）抑制Na+/Ca2+交换剂不会诱导细胞凋亡。然而，与对照组相比，CGP和TRAIL联合使用可使凋亡反应增加25倍。随着[Ca2+](m)水平的提高，细胞凋亡增加，并伴有线粒体介导的细胞凋亡特征的明显线粒体变化。钙离子载体的实验表明，仅仅增加细胞质和/或线粒体Ca2+不足以诱导细胞凋亡。这些结果具有治疗意义，因为Na+/Ca2+交换剂抑制剂被用于治疗一些神经和心脏疾病，TRAIL优先诱导癌细胞凋亡。此外，该系统为研究[Ca2+](m)在细胞凋亡中的作用提供了一个很好的模型。
Disruption of intracellular calcium initiates multiple cell-damaging processes, such as apoptosis. In normal cells, the levels of Ca2+ are low in the mitochondria, whereas in apoptotic cells, Ca2+ increases. Mitochondria uptake Ca2+ via an inner membrane channel called the uniporter and extrude it into the cytoplasm through a Na+/Ca2+ exchanger. Overload of Ca2+ in the mitochondria in CGP-treated cells leads to its damage, thus affecting cellular function and survival. The goal of these experiments was to determine the importance of mitochondrial calcium ([Ca2+](m)) in apoptosis of prostate cancer cells. Furthermore, we have examined the advantages of increasing the [Ca2+](m) and treating the cells with tumor necrosis factor related apoptosis-inducing ligand (TRAIL), a potent apoptotic agent. Our results show that, under these treatment conditions, inhibiting the Na+/Ca2+ exchanger using benzothiazepin CGP-37157 (CGP) did not induce apoptosis. However, combination of CGP and TRAIL increased the apoptotic response similar to 25-fold compared with control. Increase in apoptosis followed enhanced levels of [Ca2+](m) and was accompanied by pronounced mitochondrial changes characteristic of mitochondria-mediated apoptosis. Experiments with calcium ionophores showed that mere increase in cytosolic and/or mitochondrial Ca2+ was not sufficient to induce apoptosis. These results have therapeutic implications as inhibitors of Na+/Ca2+ exchanger are being used for treating some neurologic and cardiologic ailments, and TRAIL induces apoptosis preferentially in cancer cells. Furthermore, this system provides an excellent model to investigate the role of [Ca2+](m) in apoptosis.