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Inhibitory effects of IFN-gamma and acyclovir on the glioblastoma cell cycle

S L Kominsky1, P S Subramaniam, H M Johnson

  • 1Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, USA.

Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research
|June 7, 2000
PubMed

Insights

Acyclovir (ACV) and interferon-gamma (IFN-gamma) show significant antiproliferative effects on glioblastoma cells. This combination therapy is effective at low doses, with minimal impact on normal astrocytes, offering a promising new treatment avenue.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Glioblastoma multiforme (GBM) is an aggressive brain cancer characterized by cell cycle dysregulation.
  • Nucleoside analogs like acyclovir (ACV) are used for viral infections.
  • ACV combined with interferons (IFN) enhances efficacy in treating viral diseases.

Purpose of the Study:

  • To investigate the antiproliferative effects of acyclovir (ACV) and interferon-gamma (IFN-gamma) on glioblastoma cell lines.
  • To explore the synergistic potential of ACV and IFN-gamma in glioblastoma treatment.

Main Methods:

  • Assessed ACV's effect on glioblastoma cell lines (T98G, SNB-19, U-373) and normal human astrocytes in tissue culture.
  • Evaluated the phosphorylation efficiency of ACV in tumor cells versus normal astrocytes.
  • Investigated the combined effects of suboptimal ACV concentrations with low IFN-gamma concentrations.
  • Analyzed cell cycle progression (G1 and S phases) and molecular targets (p21WAF1/CIP1, PCNA, cyclin E/Cdk2).

Main Results:

  • High concentrations of ACV significantly inhibited glioblastoma cell growth (up to 68.3%) with less effect on normal astrocytes (38.3%).
  • Glioblastoma cells phosphorylated ACV more efficiently than normal astrocytes.
  • Suboptimal ACV concentrations combined with low IFN-gamma concentrations showed significant tumor cell growth inhibition.
  • ACV and IFN-gamma synergistically inhibited cell cycle progression in G1 and S phases.
  • The combination therapy targets DNA synthesis inhibition by ACV and induces the tumor suppressor p21WAF1/CIP1 via IFN-gamma.

Conclusions:

  • Combination therapy with suboptimal doses of IFN-gamma and ACV demonstrates significant antiproliferative effects on glioblastoma cell lines.
  • This combination exhibits minimal toxicity to normal human astrocytes, suggesting a potential therapeutic window.
  • The synergistic mechanism involves direct DNA synthesis inhibition by ACV and cell cycle arrest induced by IFN-gamma-mediated p21WAF1/CIP1 upregulation.

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