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Research Articles

Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species–mediated damage

¹ The Laboratories of Cell Growth and Function Regulation, Division of Biotechnology, College of Life Sciences and Biotechnology and ² Department of Neurosurgery, School of Medicine, Korea University, Seoul, Republic of Korea and ³ Department of Microbiology, Medical Research Institute, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea

Requests for reprints: Hyunggee Kim, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 5-ka, Anam-dong, Seongbuk-gu, Seoul 136-713, Republic of Korea. Phone: 82-2-3290-3059. E-mail: hg-kim{at}korea.ac.kr; or Jang-Bo Lee, Department of Neurosurgery, School of Medicine, Korea University, Seoul, Republic of Korea. E-mail: jangbo{at}korea.ac.kr

Abstract

We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf^–/– murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)–transduced Ink4a/Arf^–/– astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr–transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr–transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr–transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. [Mol Cancer Ther 2007;6(8):2178–87]

Grant support: Korea Food and Drug Administration grant 07132KFDA689 in 2007 and a Biogreen 21 grant (H. Kim).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/19/07; revised 5/21/07; accepted 6/29/07.