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

Abstract

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.

Hormetic Dose Response of NaAsO2 on Cell Proliferation of Prostate Cells in Vitro: Implications for Prostate Cancer Initiation and Therapy

“…The human ether-a-go-go-related gene potassium channel (hERG) has been identified as a novel regulator of growth and death in tumor cells. 13 Zhang et al 14 recently reported dual effects of arsenic trioxide on tumor cells. They reported stimulated proliferation at low doses, associated with increased expression of hERG and accelerated hERG channel activation, and inhibited proliferation at high doses, associated with reduced expression of hERG.…”

Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer

“…The proteins were visualised using an ECL Western Blotting Detection System (GE Healthcare, Buckinghamshire, England) 26 . To quantify the western blotting data, the intensities of proteins of interest in each gel were firstly normalized to their respective actin intensities, then the normalized intensities were compared with the intensity of the control group and expressed as relative values to their controls 27 .…”

Toward a broader view of mechanisms of drug cardiotoxicity

“…104 Folding inhibition also has been proposed as a mechanism of the dual tumor suppression and carcinogenicity of arsenic trioxide. 105 Similarly, the antidiarrheal berberine and its derivative, dihydroberberine (Figure 4), have been shown to impair hERG folding in both HEK293 cell lines and guinea pig ventricular cardiomyocytes. 106,107 The inhibition of folding by those drugs results in the reduction of the mature glycosylated form of 155 kDa hERG, which can be easily measured along with immature hERG (135 kDa).…”