TRAIL recombinant adenovirus triggers robust apoptosis in multidrug-resistant HL-60/Vinc cells preferentially through death receptor DR5.
TRAIL recombinant adenovirus triggers robust apoptosis in multidrug-resistant HL-60/Vinc cells preferentially through death receptor DR5.
复制标题
TRAIL 重组腺病毒优先通过死亡受体 DR5 触发多重耐药 HL-60/Vinc 细胞的强烈凋亡。
DOI：
10.1089/hum.2008.001
复制
发表时间：
2008
影响因子：
4.2
通讯作者：
Safa,AhmadR
中科院分区：
文献类型：
--
作者：
Wu,Ching-Huang;Kao,Ching-Hai;Safa,AhmadR
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)对肿瘤细胞和正常细胞具有高度选择性的诱导凋亡作用，是一种很有前途的肿瘤治疗药物。然而，一些癌细胞对重组可溶性TRAIL表现出耐药性。为了克服这一问题，我们使用TRAIL腺病毒(Ad5/35-TRAIL)诱导对药物敏感和多药耐药的HL-60白血病细胞株的凋亡，并确定了Ad5/35-TRAIL诱导凋亡的分子机制。Ad5/35-TRAIL不能诱导正常人淋巴细胞凋亡，但能诱导急性髓系白血病细胞大量凋亡。在耐药的HL-60/VEC细胞中，它比在HL-60细胞中更有效地触发了细胞的凋亡。用抗DR4和抗DR5中和抗体(尤其是抗DR5)处理的细胞减少，而抗DcR1抗体处理后，Ad5/35-TRAIL诱导的细胞凋亡增加。虽然Ad5/35-TRAIL通过激活caspase-3和caspase-10(已知将细胞死亡受体途径与线粒体途径联系起来)诱导两种细胞系的凋亡，但它仅在HL-60/VEC细胞中引发线粒体膜电位变化(Δψm)增加。Ad5/35-TRAIL还增加了在细胞凋亡中起重要作用的活性氧的产生。因此，使用Ad5/35-TRAIL可能是消除TRAIL耐药恶性细胞的有效治疗策略，这些研究可能为治疗和根除急性髓细胞白血病提供线索。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic because of its highly selective apoptosis-inducing action on neoplastic versus normal cells. However, some cancer cells express resistance to recombinant soluble TRAIL. To overcome this problem, we used a TRAIL adenovirus (Ad5/35-TRAIL) to induce apoptosis in a drug-sensitive and multidrug-resistant variant of HL-60 leukemia cells and determined the molecular mechanisms of Ad5/35-TRAIL-induced apoptosis. Ad5/35-TRAIL did not induce apoptosis in normal human lymphocytes, but caused massive apoptosis in acute myelocytic leukemia cells. It triggered more efficient apoptosis in drug-resistant HL-60/Vinc cells than in HL-60 cells. Treating the cells with anti-DR4 and anti-DR5 neutralizing antibodies (particularly anti-DR5) reduced, whereas anti-DcR1 antibody enhanced, the apoptosis triggered by Ad5/35-TRAIL. Whereas Ad5/35-TRAIL induced apoptosis in both cell lines through activation of caspase-3 and caspase-10, known to link the cell death receptor pathway to the mitochondrial pathway, it triggered increased mitochondrial membrane potential change (Δψm) only in HL-60/Vinc cells. Ad5/35-TRAIL also increased the production of reactive oxygen species, which play an important role in apoptosis. Therefore, using Ad5/35-TRAIL may be an effective therapeutic strategy for eliminating TRAIL-resistant malignant cells and these studies may provide clues to treat and eradicate acute myelocytic leukemias.