α-Tocopheryl succinate potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in human H460 lung cancer cells
α-Tocopheryl succinate potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in human H460 lung cancer cells
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DOI：
10.3858/emm.2009.41.10.080
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发表时间：
2009-10-31
影响因子：
12.8
通讯作者：
Kim, Joo Kyoung
中科院分区：
文献类型：
--
作者：
Lim, Soo-Jeong;Choi, Moon Kyung;Kim, Joo Kyoung
紫杉醇是治疗非小细胞肺癌(NSCLC)的常用化疗药物之一。在这里，我们测试了另一种有前景的抗癌药物α-生育酚琥珀酸酯(TOS)增强非小细胞肺癌细胞紫杉醇反应的能力。我们发现亚凋亡剂量的TOS极大地增强了紫杉醇诱导的人H460非小细胞肺癌细胞系的生长抑制和凋亡。我们的数据显示，这主要是由于聚(ADP-核糖)聚合酶(PARP)的裂解增加和caspase-8的激活。用z-VAD-FMK(PAN-caspase抑制剂)或z-IETD-FMK(caspase-8抑制剂)可阻断TOS/紫杉醇共处理诱导的PARP裂解和凋亡，提示TOS通过促进caspase 8激活而增强紫杉醇诱导的H460细胞凋亡。TOS/紫杉醇联合应用对人NSCLC细胞株H460、A549和H358的生长抑制作用具有协同作用。我们的观察表明，紫杉醇和TOS的联合应用可能为提高紫杉醇在非小细胞肺癌患者治疗中的疗效以及通过减少药物剂量潜在地降低紫杉醇的毒副作用提供一种新的治疗策略。
Paclitaxel is one of the chemotheraputic drugs widely used for the treatment of nonsmall cell lung cancer (NSCLC) patients. Here, we tested the ability of a-tocopheryl succinate (TOS), another promising anticancer agent, to enhance the paclitaxel response in NSCLC cells. We found that sub-apoptotic doses of TOS greatly enhanced paclitaxel-induced growth suppression and apoptosis in the human H460 NSCLC cell lines. Our data revealed that this was accounted for primarily by an augmented cleavage of poly(ADP-ribose) polymerase (PARP) and enhanced activation of caspase-8. Pretreatment with z-VAD-FMK (a pan-caspase inhibitor) or z-IETD-FMK (a caspase-8 inhibitor) blocked TOS/paclitaxel cotreatment-induced PARP cleavage and apoptosis, suggesting that TOS potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in H460 cells. Furthermore, the growth suppression effect of TOS/paclitaxel combination on human H460, A549 and H358 NSCLC cell lines were synergistic. Our observations indicate that combination of paclitaxel and TOS may offer a novel therapeutic strategy for improving paclitaxel drug efficacy in NSCLC patient therapy as well as for potentially lowering the toxic side effects of paclitaxel through reduced drug dosage.