Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation

Ching Hsein Chen, Yu Jia Chang, Maurice S B Ku, King Thom Chung, Jen Tsung Yang

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Temozolomide (TMZ) is an oral alkylating agent that has been widely used in the treatment of refractory glioma, although inherent and acquired resistance to this drug is common. The clinical use of valproic acid (VPA) as an anticonvulsant and moodstabilizing drug has been reported primarily for the treatment of epilepsy and bipolar disorder and less commonly for major depression. VPA is also used in the treatment of glioma-associated seizures with or without intracranial operation. In this study, we evaluated the potential synergistic effect of TMZ and VPA in human glioma cell lines. Compared with the use of TMZ or VPA alone, concurrent treatment with both drugs synergistically induced apoptosis in U87MG cells as evidenced by p53 and Bax expression, mitochondrial transmembrane potential loss, reactive oxygen species production, and glutathione depletion. This synergistic effect correlated with a decrease in nuclear translocation of the nuclear factor-erythroid 2 p45-related factor and corresponded with reduced heme oxygenase-1 and γ-glutamylcysteine synthetase expression. Pretreatment with N-acetylcysteine partially recovered the apoptotic effect of the TMZ/VPA combination treatment. The same degree of synergism is also seen in p53-mutant Hs683 cells, which indicates that p53 may not play a major role in the increased proapoptotic effect of the TMZ/VPA combination. In conclusion, VPA enhanced the apoptotic effect of TMZ, possibly through a redox regulation mechanism. The TMZ/VPA combination may be effective for treating glioma cancer and may be a powerful agent against malignant glioma. This drug combination should be further explored in the clinical setting.

Original languageEnglish
Pages (from-to)303-315
Number of pages13
JournalJournal of Molecular Medicine
Volume89
Issue number3
DOIs
Publication statusPublished - Mar 2011

Fingerprint

temozolomide
Valproic Acid
Glioma
Oxidation-Reduction
Apoptosis
Cell Line
Glutamate-Cysteine Ligase
Heme Oxygenase-1
Alkylating Agents
Acetylcysteine
Drug Combinations
Bipolar Disorder
Drug Resistance
Membrane Potentials
Anticonvulsants

Keywords

  • Bax
  • Glioma
  • Glutathione depletion
  • Heme oxygenase-1
  • Temozolomide
  • Valproic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. / Chen, Ching Hsein; Chang, Yu Jia; Ku, Maurice S B; Chung, King Thom; Yang, Jen Tsung.

In: Journal of Molecular Medicine, Vol. 89, No. 3, 03.2011, p. 303-315.

Research output: Contribution to journalArticle

Chen, Ching Hsein ; Chang, Yu Jia ; Ku, Maurice S B ; Chung, King Thom ; Yang, Jen Tsung. / Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. In: Journal of Molecular Medicine. 2011 ; Vol. 89, No. 3. pp. 303-315.
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