The microtubule depolymerizing agent naphthazarin induces both apoptosis and autophagy in A549 lung cancer cells
The microtubule depolymerizing agent naphthazarin induces both apoptosis and autophagy in A549 lung cancer cells
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DOI：
10.1007/s10495-011-0613-1
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发表时间：
2011-09-01
期刊：
影响因子：
7.2
通讯作者：
Chakrabarti, Gopal
中科院分区：
文献类型：
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作者：
Acharya, Bipul R.;Bhattacharyya, Surela;Chakrabarti, Gopal
萘扎苷(DHNQ，5，8-二羟基-L，4-萘醌)是一种天然可得的1，4-萘醌衍生物。在本研究中，我们着重阐明了萘扎苷对A549非小细胞肺癌细胞的细胞毒作用机制。萘扎林显著降低A549细胞的存活率，其IC50为16.4+/-A 1.6 mU，通过激活细胞凋亡和自噬途径，以剂量和时间依赖的方式诱导细胞死亡。具体地说，我们发现萘扎林抑制了PI3K/Akt细胞生存信号通路，通过P53和caspase-3的激活以及PARP的切割来衡量。它还导致Bax/Bcl2蛋白水平的比值升高，表明线粒体凋亡途径被激活。类似地，在A549细胞中，NANATHAZERING可激活LC3II的表达，并诱导自噬通量。我们进一步证明，在无细胞系统和A549细胞中，萘扎林是一种微管抑制物。萘扎林处理使间期微管解聚，纺锤体微管结构紊乱，大部分细胞停滞在G(2)/M期。综上所述，这些数据表明，萘扎林，一种激活双细胞死亡机制的微管解聚剂，可能是一种潜在的新型化疗药物。
Naphthazarin (DHNQ, 5,8-dihydroxy-l,4-naphthoquinone) is a naturally available 1,4-naphthoquinone derivatives. In this study, we focused on elucidating the cytotoxic mechanism of naphthazarin in A549 non-small cell lung carcinoma cells. Naphthazarin reduced the A549 cell viability considerably with an IC50 of 16.4 +/- A 1.6 mu M. Naphthazarin induced cell death in a dose- and time-dependent manner by activating apoptosis and autophagy pathways. Specifically, we found naphthazarin inhibited the PI3K/Akt cell survival signalling pathway, measured by p53 and caspase-3 activation, and PARP cleavage. It also resulted in an increase in the ratio of Bax/Bcl2 protein levels, indicating activation of the mitochondrial apoptotic pathway. Similarly naphthazarin triggered LC3II expression and induced autophagic flux in A549 cells. We demonstrated further that naphthazarin is a microtubule inhibitor in cell-free system and in A549 cells. Naphthazarin treatment depolymerized interphase microtubules and disorganised spindle microtubules and the majority of cells arrested at the G(2)/M transition. Together, these data suggest that naphthazarin, a microtubule depolymerizer which activates dual cell death machineries, could be a potential novel chemotherapeutic agent.