Introduction: Although temozolomide is utilized as standard chemotherapeutant against malignant gliomas, the treatment represents one of the most formidable challenges in oncology. Combination chemotherapy using temozolomide with other anti-tumor compounds are under investigation.
Methods: Synergisms of temozolomide with doxorubicin in four glioma cell lines were determined by isobologram analysis. Intracellular retention of doxorubicin in cells treated with doxorubicin +/- temozolomide was determined with flow cytometry. The expression levels of p-glycoprotein (p-gp) in glioma cells were evaluated after in vitro treatment with temozolomide. To assess the effect of temozolomide on p-gp, the p-gp ATPase assay was performed. Intracranial xenograft glioma model was used to evaluate the therapeutic benefits of temozolomide and doxorubicin.
Results: Our results showed that temozolomide significantly enhanced sensitivity to p-gp substrate in glioma cells, particularly in p-gp-overexpressed cells. Synergetic effect combining temozolomide and doxorubicin was confirmed in glioma cells. Temozolomide significantly increased the accumulation of doxorubicin in these cells. Additionally, the results of ATPase assays show that temozolomide inhibited the ATPase activity of p-gp. Furthermore, in vivo study shows that temozolomide combined with doxorubicin significantly prolonged survival of glioma-bearing rats.
Conclusions: We conclude that temozolomide reverse doxorubicin resistance by directly affecting p-gp transport activity.
Patient Care: Our findings may be useful for glioma combinational chemotherapy with temozolomide in the clinical application.
Learning Objectives: The aim of this present study was to demonstrate that temozolomide combined with doxorubicin is a promising strategy for glioblastoma.