Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt

  • Authors: Yun-Jung Choi, Jong-Wook Park, Seong-Il Suh, Kyo Cheol Mun, Jae Hoon Bae, Dae-Kyu Song, Sang-Pyo Kim, Taeg Kyu Kwon
  • View Affiliations

  • Published online on: Sunday, September 1, 2002
  • Pages: 603-610
  • DOI: 10.3892/ijo.21.3.603

Abstract

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in acute promyelocytic leukemia (APL), but little is known about the molecular mechanisms mediating these effects. In the present study, we determined the molecular pathways that lead to apoptosis after treatment of cells with arsenic trioxide. Arsenic trioxide treatment of U937 cells leads to apoptosis, which is accompanied by activation of caspase 3 (as measured by decreased levels of the 32 kDa inactive form and increased proteolytic cleavage of PLC-γ1). The broad-range caspase inhibitor z-VAD-fmk inhibits this induction of apoptosis, supporting a direct link between caspase activation and arsenic trioxide induction of apoptosis. This activation of apoptosis is accompanied by release of cytochrome c, down-regulation of cIAP1, and inactivation of Akt. Bcl-2 overexpression attenuates arsenic trioxide-induced apoptosis in U937 cells by inhibition of caspase 3 activity, but not inhibition of Akt. In addition, arsenic trioxide-induced apoptosis was caused by the generation of reactive oxygen species, which was prevented by antioxidant NAC (N-acetyl-cysteine). Co-treatment with NAC markedly prevented dephosphorylation of Akt, activation of caspase 3, and down-regulation of cIAP1. These data indicate that arsenic trioxide can cause cell damage by inactivating the Akt-related cell survival pathway and generating the reactive oxygen species, providing a new mechanism for arsenic trioxide-induced apoptosis.
Journal Cover

September 2002
Volume 21 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

2012 Impact Factor: 2.773
Ranked #31/196 Oncology
(total number of cites)

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Choi, Y., Park, J., Suh, S., Mun, K., Bae, J., Song, D., Kim, S., & Kwon, T. (2002). Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt. International Journal of Oncology, 21(3), 603-610.
MLA
Choi, Park, Suh, Mun, Bae, Song, Kim, and Taeg Kwon. "Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt." International Journal of Oncology International Journal of Oncology 21.3 (2002): 603-610.
Chicago
Choi, Park, Suh, Mun, Bae, Song, Kim, and Taeg Kwon. "Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt." International Journal of Oncology International Journal of Oncology 21 no. 3 (2002): 603-610.