Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species-mediated damage
- Authors
- Oh, Se-Yeong; Sohn, Young-Woo; Park, Jong-Whi; Park, Hyo-Jung; Jeon, Hye-Min; Kim, Tae-Kyung; Lee, Joong-Seob; Jung, Ji-Eun; Jin, Xun; Chung, Yong Gu; Choi, Young-Ki; You, Seungkwon; Lee, Jang-Bo; Kim, Hyunggee
- Issue Date
- Aug-2007
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- MOLECULAR CANCER THERAPEUTICS, v.6, no.8, pp.2178 - 2187
- Journal Title
- MOLECULAR CANCER THERAPEUTICS
- Volume
- 6
- Number
- 8
- Start Page
- 2178
- End Page
- 2187
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/83593
- DOI
- 10.1158/1535-7163.MCT-07-0111
- ISSN
- 1535-7163
- 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 11 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 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 Akt-transduced cancer cells to kill preferentially through ROS-mediated-damage.
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