Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
Int J Oncol. 2014 Nov;45(5):2033-43. doi: 10.3892/ijo.2014.2609. Epub 2014 Aug 19.
Lung cancer is one of the most common cancers worldwide. Arsenic trioxide (ATO) has been approved by the US Food and Drug Administration for the treatment of acute promyelocytic leukemia. Nonetheless preliminary data have suggested potential activity of ATO in solid tumors including lung cancer. This study aimed to examine the underlying mechanisms of ATO in the treatment of lung adenocarcinoma. Using a panel of 7 lung adenocarcinoma cell lines, the effects of ATO treatment on cell viability, expression of E2F1 and its downstream targets, phosphatidylserine externalization, mitochondrial membrane depolarization and alteration of apoptotic/anti-apoptotic factors were studied. Tumor growth inhibition in vivo was investigated using a nude mouse xenograft model. ATO decreased cell viability with clinically achievable concentrations (8 µM) in all cell lines investigated. This was accompanied by reduced expression of E2F1, cyclin A2, skp2, c-myc, thymidine kinase and ribonucleotide reductase M1, while p-c-Jun was upregulated. Cell viability was significantly decreased with E2F1 knockdown. Treatment with ATO resulted in phosphatidylserine externalization in H23 cells and mitochondrial membrane depolarization in all cell lines, associated with truncation of Bid, downregulation of Bcl-2, upregulation of Bax and Bak, caspase-9 and -3 activation and PARP cleavage. Using the H358 xenograft model, the tumor growth was suppressed in the ATO treatment group during 8 days of treatment, associated with downregulation of E2F1 and upregulation of truncated Bid and cleaved caspase-3. In conclusion, ATO has potent in vitro and in vivo activity in lung adenocarcinoma, partially mediated through E2F1 downregulation and apoptosis.
肺癌是全球最常见的癌症之一。三氧化二砷（ATO）已被美国食品和药物管理局批准用于治疗急性早幼粒细胞白血病。尽管初步数据表明 ATO 在包括肺癌在内的实体肿瘤中具有潜在活性。本研究旨在探讨 ATO 治疗肺腺癌的潜在机制。使用 7 种肺腺癌细胞系，研究了 ATO 处理对细胞活力、E2F1 及其下游靶标表达、磷脂酰丝氨酸外排、线粒体膜去极化和凋亡/抗凋亡因子改变的影响。使用裸鼠异种移植模型研究了体内肿瘤生长抑制作用。ATO 以临床可达到的浓度（8 μM）降低了所有研究细胞系的细胞活力。这伴随着 E2F1、细胞周期蛋白 A2、skp2、c-myc、胸苷激酶和核糖核苷酸还原酶 M1 的表达减少，而 p-c-Jun 上调。E2F1 敲低使细胞活力显著降低。ATO 处理导致 H23 细胞中磷脂酰丝氨酸外排和所有细胞系中线粒体膜去极化，与 Bid 截断、Bcl-2 下调、Bax 和 Bak 上调、caspase-9 和 -3 激活以及 PARP 切割有关。使用 H358 异种移植模型，ATO 治疗组在 8 天的治疗期间抑制肿瘤生长，与 E2F1 下调和截断的 Bid 和裂解的 caspase-3 上调有关。总之，ATO 在肺腺癌的体内和体外均具有强大的活性，部分通过 E2F1 下调和细胞凋亡介导。
