Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer

Fazlul H Sarkar,Aamir Ahmad,Bin Bao,Zhiwen Chen,Chuanzhong Mei,Qingling Yang,Lucio Miele,Jun Xia,Youjian Li,Zhiwei Wang

doi:10.3390/ijms13089627

Abstract

Arsenic trioxide has been reported to inhibit cell growth and induce apoptotic cell death in many human cancer cells including breast cancer. However, the precise molecular mechanisms underlying the anti-tumor activity of arsenic trioxide are still largely unknown. In the present study, we assessed the effects of arsenic trioxide on cell viability and apoptosis in breast cancer cells. For mechanistic studies, we used multiple cellular and molecular approaches such as MTT assay, apoptosis ELISA assay, gene transfection, RT-PCR, Western blotting, and invasion assays. For the first time, we found a significant reduction in cell viability in arsenic trioxide-treated cells in a dose-dependent manner, which was consistent with induction of apoptosis and also associated with down-regulation of Notch-1 and its target genes. Taken together, our findings provide evidence showing that the down-regulation of Notch-1 by arsenic trioxide could be an effective approach, to cause down-regulation of Bcl-2, and NF-κB, resulting in the inhibition of cell growth and invasion as well as induction of apoptosis. These results suggest that the anti-tumor activity of arsenic trioxide is in part mediated through a novel mechanism involving inactivation of Notch-1 and its target genes. We also suggest that arsenic trioxide could be further developed as a potential therapeutic agent for the treatment of breast cancer.

Highlights

Breast cancer is the most common malignancy in women, and the second leading cause of cancer-related mortality in women in the United States [1]
We tested the growth inhibitory effects of As2O3 using the MTT assay in three human breast cancer cell lines, MDA-MB-231, MCF-7, and SKBR-3
Treatment of breast cancer cells for 72 h with 2, 4, 6, 8, 10, and 12 μM of As2O3 led to cell growth inhibition in a dose-dependent manner in all three breast cancer cell lines (Figure 1)

Summary

Introduction

Breast cancer is the most common malignancy in women, and the second leading cause of cancer-related mortality in women in the United States [1]. The therapies for breast cancer include surgery, chemotherapy, radiation, hormonal therapy or combined modalities [2] These treatments have improved the five-year survival rate for breast cancer patients, breast cancer still suffers from long term survival, which could be due to late diagnosis, tumor metastasis, chemo- and radio-resistance, and tumor recurrence, resulting in patient death [2]. This worst outcome in a sub-group of patients suggests that it is important to identify newer and novel therapeutic agents for improving the treatment outcome with better long term survival of patients diagnosed with breast cancer. Emerging evidence has shown that activated Notch signaling pathway, and over-expression of Notch target genes are commonly observed in breast cancer [8]

Results

Discussion

Conclusion