Low Dose of Doxorubicin Potentiates the Effect of Temozolomide in Glioblastoma Cells

Mol Neurobiol. 2018 May;55(5):4185-4194. doi: 10.1007/s12035-017-0611-6. Epub 2017 Jun 13.


Glioblastoma (GBM) is an aggressive brain tumor with temozolomide (TMZ)-based chemotherapy as the main therapeutic strategy. Doxorubicin (DOX) is not used in gliomas due to its low bioavailability in the brain; however, new delivery strategies and low doses may be effective in the long term, especially as part of a drug cocktail. Our aim was to evaluate the chronic effects of low doses of DOX and TMZ in GBM. Human U87-ATCC cells and a primary GBM culture were chronically treated with TMZ (5 μM) and DOX (1 and 10 nM) alone or combined. DOX resulted in a reduction in the number of cells over a period of 35 days and delayed the cell regrowth. In addition, DOX induced cell senescence and reduced tumor sphere formation and the proportion of NANOG- and OCT4-positive cells after 7 days. Low doses of TMZ potentiated the effects of DOX on senescence and sphere formation. This combined response using low doses of DOX may pave the way for its use in glioma therapy, with new technologies to overcome its low blood-brain barrier permeability.

Keywords: Cancer stem cell; Cell proliferation; Cell senescence; Doxorubicin; Glioblastoma; Temozolomide.

MeSH terms

  • Brain Neoplasms / pathology*
  • Cell Count
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology*
  • Glioblastoma / pathology*
  • Humans
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Temozolomide / pharmacology*


  • Doxorubicin
  • Temozolomide