Endocrinology Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
Medicinal and Process Chemistry Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
Free Radic Biol Med. 2014 Mar;68:288-301. doi: 10.1016/j.freeradbiomed.2013.12.016. Epub 2013 Dec 27.
The natural polyphenolic alkanone (6)-gingerol (6G) has established anti-inflammatory and antitumoral properties. However, its precise mechanism of action in myeloid leukemia cells is unclear. In this study, we investigated the effects of 6G on myeloid leukemia cells in vitro and in vivo. The results of this study showed that 6G inhibited proliferation of myeloid leukemia cell lines and primary myeloid leukemia cells while sparing the normal peripheral blood mononuclear cells, in a concentration- and time-dependent manner. Mechanistic studies using U937 and K562 cell lines revealed that 6G treatment induced reactive oxygen species (ROS) generation by inhibiting mitochondrial respiratory complex I (MRC I), which in turn increased the expression of the oxidative stress response-associated microRNA miR-27b and DNA damage. Elevated miR-27b expression inhibited PPARγ, with subsequent inhibition of the inflammatory cytokine gene expression associated with the oncogenic NF-κB pathway, whereas the increased DNA damage led to G2/M cell cycle arrest. The 6G induced effects were abolished in the presence of anti-miR-27b or the ROS scavenger N-acetylcysteine. In addition, the results of the in vivo xenograft experiments in mice indicated that 6G treatment inhibited tumor cell proliferation and induced apoptosis, in agreement with the in vitro studies. Our data provide new evidence that 6G-induced myeloid leukemia cell death is initiated by reactive oxygen species and mediated through an increase in miR-27b expression and DNA damage. The dual induction of increased miR-27b expression and DNA damage-associated cell cycle arrest by 6G may have implications for myeloid leukemia treatment.
天然多酚烷酮（6）-姜烯酚（6G）具有抗炎和抗肿瘤特性。然而，其在髓系白血病细胞中的确切作用机制尚不清楚。在这项研究中，我们研究了 6G 对体外和体内髓系白血病细胞的影响。研究结果表明，6G 以浓度和时间依赖性方式抑制髓系白血病细胞系和原代髓系白血病细胞的增殖，而对正常外周血单个核细胞无影响。使用 U937 和 K562 细胞系进行的机制研究表明，6G 通过抑制线粒体呼吸复合物 I（MRC I）诱导活性氧（ROS）的产生，从而增加与氧化应激反应相关的 microRNA miR-27b 的表达和 DNA 损伤。miR-27b 表达的升高抑制了 PPARγ，随后抑制了与致癌 NF-κB 途径相关的炎症细胞因子基因表达，而增加的 DNA 损伤导致 G2/M 细胞周期停滞。在存在抗 miR-27b 或 ROS 清除剂 N-乙酰半胱氨酸的情况下，6G 诱导的作用被消除。此外，在小鼠体内异种移植实验的结果表明，6G 处理抑制肿瘤细胞增殖并诱导细胞凋亡，与体外研究一致。我们的数据提供了新的证据，表明 6G 诱导的髓系白血病细胞死亡是由活性氧引发的，并通过增加 miR-27b 表达和 DNA 损伤介导的。6G 诱导的增加 miR-27b 表达和与 DNA 损伤相关的细胞周期停滞的双重诱导可能对髓系白血病的治疗具有重要意义。
