Activation of polyamine catabolism by N1,N11-diethylnorspermine leads to cell death in glioblastoma

  • Authors:
    • Rongcai Jiang
    • Woonyoung Choi
    • Asad Khan
    • Kenneth Hess
    • Eugene W. Gerner
    • Robert A. Casero
    • W. K.Alfred Yung
    • Stanley R. Hamilton
    • Wei Zhang
  • View Affiliations

  • Published online on: August 1, 2007     https://doi.org/10.3892/ijo.31.2.431
  • Pages: 431-440
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Abstract

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 N1,N11-diethyl-norspermine (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 H2O2 production, which is a potential target for GBM therapy.

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August 2007
Volume 31 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Jiang R, Choi W, Khan A, Hess K, Gerner EW, Casero RA, Yung WK, Hamilton SR and Zhang W: Activation of polyamine catabolism by N1,N11-diethylnorspermine leads to cell death in glioblastoma. Int J Oncol 31: 431-440, 2007
APA
Jiang, R., Choi, W., Khan, A., Hess, K., Gerner, E.W., Casero, R.A. ... Zhang, W. (2007). Activation of polyamine catabolism by N1,N11-diethylnorspermine leads to cell death in glioblastoma. International Journal of Oncology, 31, 431-440. https://doi.org/10.3892/ijo.31.2.431
MLA
Jiang, R., Choi, W., Khan, A., Hess, K., Gerner, E. W., Casero, R. A., Yung, W. K., Hamilton, S. R., Zhang, W."Activation of polyamine catabolism by N1,N11-diethylnorspermine leads to cell death in glioblastoma". International Journal of Oncology 31.2 (2007): 431-440.
Chicago
Jiang, R., Choi, W., Khan, A., Hess, K., Gerner, E. W., Casero, R. A., Yung, W. K., Hamilton, S. R., Zhang, W."Activation of polyamine catabolism by N1,N11-diethylnorspermine leads to cell death in glioblastoma". International Journal of Oncology 31, no. 2 (2007): 431-440. https://doi.org/10.3892/ijo.31.2.431