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

Abstract

We have established several glioma-relevant oncogeneengineered cancer cells to reevaluate the oncogeneselective 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 À/À murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr) -transduced Ink4a/Arf À/À 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 etoposideselective 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 Akttransduced cancer cells to kill preferentially through ROSmediated damage.

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