Sensitizing the Cell Killing Effects of Doxorubicin as a Possible Therapeutic Strategy Against Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM), the most common type of brain cancer, is also the deadliest of all cancers, having 5-year survival rates of less than 10%. Standard therapy for GBM includes surgery followed by ionizing radiation and treatment with temozolomide, a DNA alkylating agent. Unfortunately, even with aggressive treatments with these modalities, the median survival time for most GBM patients is less than 16 months. This study examines a new treatment strategy by combining doxorubicin, a soluble DNA-damaging agent that produces double-stranded DNA like ionizing radiation, with an artificial nucleoside designated 5-nitroindolyl-2deoxyriboside (5-NIdR) that inhibits the misreplication of DNA lesions produced by the drug. Cell-based studies with grade 3 and grade 4 astrocytomas demonstrate that combining 5-NIdR with doxorubicin improves the cell-killing effects of the drug by increasing apoptosis. Flow cytometry experiments demonstrate that 5-NIdR does not increase the level of reactive oxygen species produced by doxorubicin. Instead, the increase in cell death produced by combining the two agents likely reflects inhibiting the replication of damaged DNA. Consistent with this mechanism, cell-cycle experiments demonstrate that this combination blocks cells at Go/G1, suggesting that 5-NIdR interferes with DNA polymerase activity during the repair of double-strand DNA breaks. The ability of 5-NIdR to inhibit double-strand DNA break repair could be extended to other modalities used to treat brain cancer such as ionizing radiation. Furthermore, the chemosensitizing effect of 5-NIdR could improve the overall efficacy of doxorubicin by lowering the risk of side effects caused by the DNA-damaging agent.