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

Se Yeong Oh, Young Woo Sohn, Jong Whi Park, Hyo Jung Park, Hye Min Jeon, Tae Kyung Kim, Joong Seob Lee, Ji Eun Jung, Xun Jin, Gu Chung Yong, Young Ki Choi, Seungkwon You, Jang Bo Lee, Hyunggee Kim

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34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2178-2187
Number of pages10
JournalMolecular cancer therapeutics
Volume6
Issue number8
DOIs
Publication statusPublished - 2007 Aug 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Oh, S. Y., Sohn, Y. W., Park, J. W., Park, H. J., Jeon, H. M., Kim, T. K., Lee, J. S., Jung, J. E., Jin, X., Yong, G. C., Choi, Y. K., You, S., Lee, J. B., & Kim, H. (2007). Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species-mediated damage. Molecular cancer therapeutics, 6(8), 2178-2187. https://doi.org/10.1158/1535-7163.MCT-07-0111