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Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer
Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu 233030, China
Laboratory Medicine, Taixing People’s Hospital, Taizhou 225400, China
Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu 233030, China
Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
University of Mississippi Cancer Institute, 2500 N State St, Jackson, MS 39216, USA
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 30 May 2012; in revised form: 15 July 2012 / Accepted: 25 July 2012 / Published: 2 August 2012
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.
Keywords: Notch; arsenic trioxide; NF-κB; breast cancer; apoptosis; cell growth
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Xia, J.; Li, Y.; Yang, Q.; Mei, C.; Chen, Z.; Bao, B.; Ahmad, A.; Miele, L.; Sarkar, F.H.; Wang, Z. Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. Int. J. Mol. Sci. 2012, 13, 9627-9641.
Xia J, Li Y, Yang Q, Mei C, Chen Z, Bao B, Ahmad A, Miele L, Sarkar FH, Wang Z. Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer. International Journal of Molecular Sciences. 2012; 13(8):9627-9641.
Xia, Jun; Li, Youjian; Yang, Qingling; Mei, Chuanzhong; Chen, Zhiwen; Bao, Bin; Ahmad, Aamir; Miele, Lucio; Sarkar, Fazlul H; Wang, Zhiwei. 2012. "Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer." Int. J. Mol. Sci. 13, no. 8: 9627-9641.