Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species mediated damage.
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.
Oh
Se-Yeong
SY
Breast Cancer Translational Research Laboratory, College of Life Sciences and Biotechnology, Korea University, 5-ka, Anam-dong, Seongbuk-gu, Seoul 136-713, Republic of Korea.
Sohn
Young-Woo
YW
Park
Jong-Whi
JW
Park
Hyo-Jung
HJ
Jeon
Hye-Min
HM
Kim
Tae-Kyung
TK
Lee
Joong-Seob
JS
Jung
Ji-Eun
JE
Jin
Xun
X
Chung
Yong Gu
YG
Choi
Young-Ki
YK
You
Seungkwon
S
Lee
Jang-Bo
JB
Kim
Hyunggee
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D010436:Pepstatins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010436:Pepstatins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D051058:Oncogene Protein v-akt; C031375:pepstatin