LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells.
LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells.
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DOI：
10.3892/mmr.2015.3862
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发表时间：
2015-09
影响因子：
3.4
通讯作者：
Takai Y
中科院分区：
文献类型：
--
作者：
Sato M;Hirose K;Kashiwakura I;Aoki M;Kawaguchi H;Hatayama Y;Akimoto H;Narita Y;Takai Y
缺氧诱导因子1（HIF-1）激活基因的转录，这些基因作用于癌细胞对缺氧的适应。LW 6是一种HIF-1抑制剂，被假设通过抑制HIF-1α的积累来改善缺氧肿瘤对癌症治疗的抗性。在低氧条件下的明显抗肿瘤作用表明LW 6可能是低氧条件下癌症的改进治疗策略。在本研究中，LW 6对A549肺癌细胞的生长和凋亡的HIF-1抑制潜力与氧可用性进行了评估。观察到LW 6在20 mM下抑制A549细胞中缺氧诱导的HIF-1α表达，与von Hippel-Lindau蛋白无关。此外，在此浓度下，LW 6诱导缺氧选择性细胞凋亡连同线粒体膜电位的降低。在LW 6处理的缺氧A549细胞中，细胞内活性氧水平增加，LW 6诱导线粒体O2·−的缺氧选择性增加。结论：LW 6通过影响线粒体抑制缺氧A549细胞的生长。线粒体呼吸链的抑制被认为是靶向癌细胞凋亡的潜在有效策略。
Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that act upon the adaptation of cancer cells to hypoxia. LW6, an HIF-1 inhibitor, was hypothesized to improve resistance to cancer therapy in hypoxic tumors by inhibiting the accumulation of HIF-1α. A clear anti-tumor effect under low oxygen conditions would indicate that LW6 may be an improved treatment strategy for cancer in hypoxia. In the present study, the HIF-1 inhibition potential of LW6 on the growth and apoptosis of A549 lung cancer cells in association with oxygen availability was evaluated. LW6 was observed to inhibit the expression of HIF-1α induced by hypoxia in A549 cells at 20 mM, independently of the von Hippel-Lindau protein. In addition, at this concentration, LW6 induced hypoxia-selective apoptosis together with a reduction in the mitochondrial membrane potential. The intracellular reactive oxygen species levels increased in LW6-treated hypoxic A549 cells and LW6 induced a hypoxia-selective increase of mitochondrial O2•−. In conclusion, LW6 inhibited the growth of hypoxic A549 cells by affecting the mitochondria. The inhibition of the mitochondrial respiratory chain is suggested as a potentially effective strategy to target apoptosis in cancer cells.