Dual effects of arsenic trioxide on tumor cells and the potential underlying mechanisms

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 As₂O₃ (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.