Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis.
Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis.
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DOI：
10.1038/cddis.2013.179
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发表时间：
2013-06-06
影响因子：
9
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中科院分区：
文献类型：
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静息肿瘤细胞由于其增加的治疗抗性而在抗癌治疗期间代表了巨大的挑战。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种公认的未来抗癌药物，目前正在进行I期和II期临床研究。我们最近表明，TRAIL能够靶向白血病干细胞替代物。在这里，我们测试了TRAIL靶向细胞周期停滞的肿瘤细胞的能力。用细胞毒药物、时相特异性抑制剂或针对cyclinB和E的RNA干扰诱导肿瘤细胞系和异种移植肿瘤细胞的细胞周期停滞在G0、G1或G2。在细胞周期的任何点的生物化学或分子停滞增加TRAIL诱导的凋亡。因此，当通过添加咖啡因使细胞周期停滞失效时，TRAIL的抗肿瘤活性降低。对于临床转化最重要的是，来自三名患有B前体或T细胞急性淋巴细胞白血病的儿童的肿瘤细胞显示，在敲低细胞周期蛋白B或细胞周期蛋白E后，TRAIL诱导的凋亡增加，分别将细胞周期阻滞在G2或G1期。总之，与大多数常规细胞毒性药物相比，TRAIL对细胞周期停滞的肿瘤细胞发挥增强的抗肿瘤活性。因此，TRAIL可能代表一种有趣的药物来治疗静止肿瘤疾病，例如，在微小残留病变期间。
Resting tumor cells represent a huge challenge during anticancer therapy due to their increased treatment resistance. TNF-related apoptosis-inducing ligand (TRAIL) is a putative future anticancer drug, currently in phases I and II clinical studies. We recently showed that TRAIL is able to target leukemia stem cell surrogates. Here, we tested the ability of TRAIL to target cell cycle-arrested tumor cells. Cell cycle arrest was induced in tumor cell lines and xenografted tumor cells in G0, G1 or G2 using cytotoxic drugs, phase-specific inhibitors or RNA interference against cyclinB and E. Biochemical or molecular arrest at any point of the cell cycle increased TRAIL-induced apoptosis. Accordingly, when cell cycle arrest was disabled by addition of caffeine, the antitumor activity of TRAIL was reduced. Most important for clinical translation, tumor cells from three children with B precursor or T cell acute lymphoblastic leukemia showed increased TRAIL-induced apoptosis upon knockdown of either cyclinB or cyclinE, arresting the cell cycle in G2 or G1, respectively. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts enhanced antitumor activity against cell cycle-arrested tumor cells. Therefore, TRAIL might represent an interesting drug to treat static-tumor disease, for example, during minimal residual disease.
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