Zhang Xiao, Yu Dahai, Geng Huaize, Li Fengmei, Lv Lin, Zhao Lei, Yan Caichuan, Li Baoxin
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
The State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
Oncol Lett. 2018 Sep;16(3):3812-3820. doi: 10.3892/ol.2018.9086. Epub 2018 Jul 5.
The human ether-a-go-go related gene (hERG) encodes the rapid delayed rectifier K channel. hERG not only serves an important role in heart muscle and cardiomyocyte excitability by regulating action potential repolarization, but also represents a selective advantage for cancer cell proliferation. Arsenic trioxide is a traditional Chinese medicine, which has been previously identified as an efficient tumor suppressor, particularly in the treatment of acute pro-myelocytic leukemia. However, studies have also reported that long-term exposure to arsenicals may lead to the formation of malignant tumors. In the present study, the effect of low-dose arsenic trioxide on the proliferation and apoptosis of tumor cells was investigated, as were the potential underlying mechanisms of this effect. The data demonstrated that low-dose arsenic trioxide (0.1 µM) enhanced the viability and apoptosis of tumor cells expressing hERG channels following long-term incubation. However, in tumor cells lacking hERG channels, low-dose arsenic trioxide had no effect. Therefore, we hypothesized that this hormesis effect of low-dose arsenic trioxide on tumor cells may be associated with the hERG channel. Furthermore, low dose arsenic trioxide promoted the hERG-channel current by changing the kinetics of channel gating and prolonging the open-channel stage. Simultaneously, high-dose AsO (1 or 10 µM) significantly reduced the expression of hERG in tumor cells compared with the control group, which resulted in reduced proliferation rate and promotion of apoptotic rate. The results of the present study demonstrate that the dual effects of arsenic trioxide on hERG channels vary according to concentration, resulting in the dual effects on tumor cells. This provides a theoretical basis for the potential clinical application of arsenic trioxide, suggesting that hERG channels are an important target in preventing and treating tumorigenesis during arsenicosis.
人类醚 - 去极化相关基因（hERG）编码快速延迟整流钾通道。hERG不仅通过调节动作电位复极化在心肌和心肌细胞兴奋性中发挥重要作用，而且对癌细胞增殖具有选择性优势。三氧化二砷是一种传统中药，先前已被确定为一种有效的肿瘤抑制剂，特别是在治疗急性早幼粒细胞白血病方面。然而，研究也报道长期接触砷化合物可能导致恶性肿瘤的形成。在本研究中，研究了低剂量三氧化二砷对肿瘤细胞增殖和凋亡的影响及其潜在机制。数据表明，长期孵育后，低剂量三氧化二砷（0.1μM）可增强表达hERG通道的肿瘤细胞的活力和凋亡。然而，在缺乏hERG通道的肿瘤细胞中，低剂量三氧化二砷没有作用。因此，我们推测低剂量三氧化二砷对肿瘤细胞的这种兴奋效应可能与hERG通道有关。此外，低剂量三氧化二砷通过改变通道门控动力学和延长开放通道阶段来促进hERG通道电流。同时，与对照组相比，高剂量AsO（1或10μM）显著降低肿瘤细胞中hERG的表达，导致增殖率降低和凋亡率升高。本研究结果表明，三氧化二砷对hERG通道的双重作用因浓度而异，从而对肿瘤细胞产生双重影响。这为三氧化二砷的潜在临床应用提供了理论依据，表明hERG通道是预防和治疗砷中毒过程中肿瘤发生的重要靶点。
