TY - JOUR
T1 - Activation of polyamine catabolism by N1,N11- diethylnorspermine leads to cell death in glioblastoma
AU - Jiang, Rongcai
AU - Choi, Woonyoung
AU - Khan, Asad
AU - Hess, Kenneth
AU - Gerner, Eugene W.
AU - Casero, Robert A.
AU - Yung, W. K.Alfred
AU - Hamilton, Stanley R.
AU - Zhang, Wei
PY - 2007/8
Y1 - 2007/8
N2 - Glioblastoma multiforme (GBM) is one of the most therapeutically refractory human cancers. Elevated cellular polyamine levels are a common feature of cancer cells, including GBM cells, and the polyamine pathway has been explored as a potential therapeutic target to inhibit polyamine biosynthesis or activate polyamine catabolism. In this study, we investigated the effect of N 1,N11-diethylnorspermine (DENSPM), a spermine analog that activates polyamine catabolism, in GBM cells. The in vitro cell culture experiments showed that DENSPM increased the sub-G1 apoptotic cell population in GBM cell lines but caused minimal cytotoxicity in normal astrocytes. Prior to apoptosis induction, DENSPM caused the elevation of spermidine/spermine N1-acetyltransferase (SSAT) expression accompanied by a decrease in polyamine levels and an increase of acetylated polyamine levels, which temporally coincided with the onset of hydrogen peroxide (H2O2) induction in the cells. The cytotoxic effects of DENSPM in the GBM cells could be partially attenuated by either turning down SSAT mRNA with small interference RNA or inhibiting H2O2 production with N1-acetylpolymine oxidase (APAO)/spermine oxidase (SMO) inhibitor. Though mitochondrial damage was induced, neither activation of the caspase cascade nor cytochrome c redistribution between the mitochondria and cytoplasm was observed. Systemic DENSPM treatment of mice with intracerebral GBM led to longer survival. Taken together, our studies indicate that DENSPM kills GBM cells through induction of SSAT coupled with H2O 2 production, which is a potential target for GBM therapy.
AB - Glioblastoma multiforme (GBM) is one of the most therapeutically refractory human cancers. Elevated cellular polyamine levels are a common feature of cancer cells, including GBM cells, and the polyamine pathway has been explored as a potential therapeutic target to inhibit polyamine biosynthesis or activate polyamine catabolism. In this study, we investigated the effect of N 1,N11-diethylnorspermine (DENSPM), a spermine analog that activates polyamine catabolism, in GBM cells. The in vitro cell culture experiments showed that DENSPM increased the sub-G1 apoptotic cell population in GBM cell lines but caused minimal cytotoxicity in normal astrocytes. Prior to apoptosis induction, DENSPM caused the elevation of spermidine/spermine N1-acetyltransferase (SSAT) expression accompanied by a decrease in polyamine levels and an increase of acetylated polyamine levels, which temporally coincided with the onset of hydrogen peroxide (H2O2) induction in the cells. The cytotoxic effects of DENSPM in the GBM cells could be partially attenuated by either turning down SSAT mRNA with small interference RNA or inhibiting H2O2 production with N1-acetylpolymine oxidase (APAO)/spermine oxidase (SMO) inhibitor. Though mitochondrial damage was induced, neither activation of the caspase cascade nor cytochrome c redistribution between the mitochondria and cytoplasm was observed. Systemic DENSPM treatment of mice with intracerebral GBM led to longer survival. Taken together, our studies indicate that DENSPM kills GBM cells through induction of SSAT coupled with H2O 2 production, which is a potential target for GBM therapy.
KW - Glioblastoma
KW - Polyamine
UR - http://www.scopus.com/inward/record.url?scp=35148831760&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35148831760&partnerID=8YFLogxK
U2 - 10.3892/ijo.31.2.431
DO - 10.3892/ijo.31.2.431
M3 - Article
C2 - 17611701
AN - SCOPUS:35148831760
SN - 1019-6439
VL - 31
SP - 431
EP - 440
JO - International journal of oncology
JF - International journal of oncology
IS - 2
ER -