Inhibitory effects of IFN-gamma and acyclovir on the glioblastoma cell cycle.
Glioblastoma multiforme is one of the most aggressive and frequently occurring forms of brain cancer. It originates from astrocytes and is characterized by a loss of cell cycle control frequently involving mutations in tumor suppressor genes, such as p53 and p16. Nucleoside analogs, such as acyclovir (ACV), are currently being used in the treatment of viral diseases, such as those caused by members of the herpes family. Further, ACV in combination with type I interferons (IFN) has been shown to be more effective at lower doses in treatment of viral diseases. We show here that ACV at high concentrations (up to 500 microg/ml) inhibited growth in tissue culture of the human glioblastoma cell lines T98G, SNB-19, and U-373 by as much as 68.3% while inhibiting normal human astrocytes by only 38.3%. Related to this, the tumor cells were more than sevenfold more efficient in phosphorylation of ACV to the active phosphate form than normal human astrocytes. Analogous to treatment of virus-infected cells, suboptimal concentrations of ACV were as effective as high concentrations when used in conjunction with low concentrations of IFN-gamma in inhibition of tumor cell growth. At the cellular level, ACV and IFN-gamma inhibited the cell cycle in both the G1 and S phases. The cooperative effect of ACV and IFN-gamma against the glioblastomas appears to be due to direct inhibition of DNA synthesis by ACV in the S phase of the cell cycle and induction by IFN-gamma of the tumor suppressor gene p21wAF1/CIP1, which in turn acts at the level of proliferating cell nuclear antigen (PCNA) and cyclin E/cyclin-dependent kinase 2 (Cdk2) binding and inhibition of function. These studies show that the combination of IFN-gamma and ACV at suboptimal concentrations elicits significant antiproliferative effects on the glioblastoma cell lines T98G, SNB-19, and U-373 while having very little effect on normal human astrocyte cell proliferation.
Kominsky
S L
SL
Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, USA.
Subramaniam
P S
PS
Johnson
H M
HM
Torres
B A
BA
D000212:Acyclovir / Q000008:administration & dosage*; D000998:Antiviral Agents / Q000008:administration & dosage; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000212:Acyclovir